2-substituted-6-amino-5-alkyl, alkenyl or alkynyl-4-pyrimidinecarboxylic acids and 6-substituted-4-amino-3-alkyl, alkenyl or alkynyl picolinic acids and their use as herbicides

ABSTRACT

6-Amino-4-pyrimidinecarboxylic acids having alkyl, alkenyl or alkynyl substituents in the 5-position and 4-aminopicolinic acids having alkyl, alkenyl or alkynyl substituents in the 3-position, and their amine and acid derivatives, are potent herbicides demonstrating a broad spectrum of weed control.

This application is a continuation application of U.S. Ser. No.12/581,913 filed on Oct. 20, 2009, which is a divisional application ofU.S. Ser. No. 12/243,469 filed on Oct. 1, 2008, and claims the benefitof U.S. Provisional Application Ser. No. 60/997,210 filed on Oct. 2,2007 and U.S. Provisional Application Ser. No. 61/049,536 filed on May1, 2008.

BACKGROUND OF THE INVENTION

This invention relates to certain novel2-(substituted)-6-amino-5-(alkyl, alkenyl oralkynyl)-4-pyrimidine-carboxylates and 6-(substituted)-4-amino-3-(alkyl,alkenyl or alkynyl) picolinates and their derivatives and to the use ofthese compounds as herbicides.

A number of pyrimidine carboxylic acids and their pesticidal propertieshave been described in the art. WO 2005/063721 A1, WO 2007/092184 A2 andU.S. Pat. No. 7,300,907 B2 disclose a genus of2-substituted-6-amino-4-pyrimidinecarboxylic acids and their derivativeswith halogen, cyano, thiocyanato, nitro, alkyl, haloalkyl, alkoxy,thioalkyl and amino substituents in the 5-position and their use asherbicides.

A number of picolinic acids and their pesticidal properties have beendescribed in the art. U.S. Pat. Nos. 6,297,197 B1; 6,784,137 B2; and7,314,849 B2 and US Patent Application Publication 2004/0198608 A1disclose a genus of 6-substituted-4-aminopicolinic acids and theirderivatives with halogen, cyano, thiocyanato, nitro, alkyl, haloalkyl,alkoxy, haloalkoxy, thioalkyl and aryloxy substituents in the 3-positionand their use as herbicides.

SUMMARY OF THE INVENTION

It has now been found that certain 2-(substituted)-6-amino-5-(alkyl,alkenyl or alkynyl)-4-pyrimidinecarboxylic acids and6-(substituted)-4-amino-3-(alkyl, alkenyl or alkynyl) picolinic acidsand their derivatives are superior herbicides with a broad spectrum ofweed control against woody plants, grasses and sedges as well asbroadleaf weeds and with excellent selectivity to beneficial plantspecies. The compounds further possess excellent toxicological orenvironmental profiles.

The invention includes compounds of Formula I:

wherein

A represents N or CR₅;

R₁ represents C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₂-C₄ alkoxyalkyl, C₂-C₄alkylhioalkyl, C₂-C₄ alkenyl, C₂-C₄ haloalkenyl, C₂-C₄ alkoxyalkenyl,C₂-C₄ thioalkylalkenyl, C₂-C₄ alkynyl or C₂-C₄ haloalkynyl, formyl,C₂-C₄ alkylcarbonyl, C₂-C₄ haloalkylcarbonyl;

R₂ represents C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆haloalkenyl or

wherein

W₁ represents H or halogen;

X₁ represents H, halogen, nitro, cyano, formyl, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, C₂-C₄ alkoxyalkyl, C₂-C₆alkylcarbonyl, C₁-C₆ alkylhio, C₁-C₆ alkylsulfinyl, C₁-C₆ alkylsulfonyl,C₂-C₄ alkenyloxy, C₂-C₄ alkynloxy, C₂-C₄ alkenylthio, C₂-C₄ alkynylthio,C₁-C₆ haloalkyl, C₂-C₆ halo-alkenyl, C₂-C₆ haloalkynyl, C₁-C₆haloalkoxy, C₂-C₄ haloalkoxyalkyl, C₂-C₆ haloalkylcarbonyl, C₁-C₆haloalkylthio, C₁-C₆ haloalkylsulfinyl, C₁-C₆ halo-alkylsulfonyl, C₃-C₆trialkylsilyl, C₂-C₄ haloalkenyloxy, C₂-C₄ haloalkynyloxy, C₂-C₄haloalkenylthio, C₂-C₄ haloalkynylthio, —C(O)OR₇, —C(O)NR₆R₇, —CR₆NOR₇,—NR₆R₇, —NR₆OR₇, —NR₆SO₂R₇, —NR₆C(O)R₇, —NR₆C(O)OR₇, —NR₆C(O)NR₆R₇ or—NCR₆NR₆R₇;

Y₁ represents H, halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, C₂-C₆ alkenyl or C₂-C₆ haloalkenyl, or, when X₁ and Y₁are taken together, represents —O(CH₂)_(n)CH₂—, or —O(CH₂)_(n)O— whereinn=1 or 2; and

Z₁ represents H or halogen;

R₃ and R₄ independently represent H, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆alkynyl, hydroxy, C₁-C₆ alkoxy, amino, C₁-C₆ acyl, C₁-C₆ carboalkoxy,C₁-C₆ alkylcarbamyl, C₁-C₆ alkylsulfonyl, C₁-C₆ trialkylsilyl or C₁-C₆dialkyl phosphonyl or R₃ and R₄ taken together with N represent a 5- or6-membered saturated ring; and

R₅ represents H or halogen;

R₆ represents H, C₁-C₄ alkyl or C₁-C₄ haloalkyl; and

R₇ represents C₁-C₄ alkyl or C₁-C₄ haloalkyl;

and agriculturally acceptable derivatives of the carboxylic acid group.

Preferred compounds of formula (I) include the following classes:

(1) Compounds of formula (I) wherein R₁ is C₁-C₂ alkyl, C₁-C₂ haloalkyl,C₂-C₃ alkenyl or C₂-C₃ haloalkenyl, most preferably wherein R₁ is vinyl.

(2) Compounds of formula (I) wherein R₂ is cyclopropyl.

(3) Compounds of formula (I) wherein R₂ is

(4) Compounds of class (3) wherein W₁ represents H or F, X₁ representsH, halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxyor —NR₆R₇, Y₁ represents Cl or halomethyl, and Z₁ represents H or F.

(5) Compounds of formula (I) wherein R₃ and R₄ are H or C₁-C₆ alkyl.

It will be appreciated by those skilled in the art that the mostpreferred compounds are generally those which are comprised ofcombinations of the above preferred classes.

The invention includes herbicidal compositions comprising anherbicidally effective amount of a compound of Formula I andagriculturally acceptable derivatives of the carboxylic acid group in amixture with an agriculturally acceptable adjuvant or carrier. Theinvention also includes a method of use of the compounds andcompositions of the present invention to kill or control undesirablevegetation by application of an herbicidal amount of the compound to thevegetation or to the locus of the vegetation as well as to the soilprior to emergence of the vegetation.

DETAILED DESCRIPTION OF THE INVENTION

The herbicidal compounds of the present invention are derivatives of6-amino-5-(alkyl, alkenyl or alkynyl)-4-pyrimidinecarboxylic acids or4-amino-3-(alkyl, alkenyl or alkynyl) picolinic acids of the formula:

wherein

A represents N or CR₅;

R₁ represents C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₂-C₄ alkoxyalkyl, C₂-C₄alkylhioalkyl, C₂-C₄ alkenyl, C₂-C₄ haloalkenyl, C₂-C₄ alkoxyalkenyl,C₂-C₄ thioalkylalkenyl, C₂-C₄ alkynyl or C₂-C₄ haloalkynyl, formyl,C₂-C₄ alkylcarbonyl, C₂-C₄ haloalkylcarbonyl;

R₂ represents C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆haloalkenyl or

wherein

W₁ represents H or halogen;

X₁ represents H, halogen, nitro, cyano, formyl, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, C₂-C₄ alkoxyalkyl, C₂-C₆alkylcarbonyl, C₁-C₆ alkylhio, C₁-C₆ alkylsulfinyl, C₁-C₆ alkylsulfonyl,C₂-C₄ alkenyloxy, C₂-C₄ alkynloxy, C₂-C₄ alkenylthio, C₂-C₄ alkynylthio,C₁-C₆ haloalkyl, C₂-C₆ haloalkenyl, C₂-C₆ haloalkynyl, C₁-C₆ haloalkoxy,C₂-C₄ haloalkoxyalkyl, C₂-C₆ haloalkylcarbonyl, C₁-C₆ haloalkylthio,C₁-C₆ haloalkylsulfinyl, C₁-C₆ halo-alkylsulfonyl, C₃-C₆ trialkylsilyl,C₂-C₄ haloalkenyloxy, C₂-C₄ haloalkynyloxy, C₂-C₄ haloalkenylthio, C₂-C₄haloalkynylthio, —C(O)OR₇, —C(O)NR₆R₇, —CR₆NOR₇, —NR₆R₇, —NR₆OR₇,—NR₆SO₂R₇, —NR₆C(O)R₇, —NR₆C(O)OR₇, —NR₆C(O)NR₆R₇ or —NCR₆NR₆R₇;

Y₁ represents H, halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, C₂-C₆ alkenyl or C₂-C₆ haloalkenyl, or, when X₁ and Y₁are taken together, represents —O(CH₂)_(n)CH₂—, or —O(CH₂)_(n)O— whereinn=1 or 2; and

Z₁ represents H or halogen;

R₅ represents H or halogen

R₆ represents H, C₁-C₄ alkyl or C₁-C₄ haloalkyl; and

R₇ represents C₁-C₄ alkyl or C₁-C₄ haloalkyl;

The amino group at the 6-position of the pyrimidine ring or the4-position of the pyridine ring can be unsubstituted or substituted withone or more C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, hydroxy, C₁-C₆alkoxy or amino substituents. The amino group can be further derivatizedas an amide, a carbamate, a urea, a sulfonamide, a silylamine or aphosphoramidate. Such derivatives are capable of breaking down into theamine. An unsubstituted amino group or one substituted with one or twoalkyl substituents is preferred.

The carboxylic acids of Formula Ia are believed to be the compounds thatactually kill or control undesirable vegetation and are typicallypreferred. Analogs of these compounds in which the acid group of thepyrimidine carboxylic acid or picolinic acid is derivatized to form arelated substituent that can be transformed within plants or theenvironment to an acid group possess essentially the same herbicidaleffect and are within the scope of the invention. Therefore, an“agriculturally acceptable derivative”, when used to describe thecarboxylic acid functionality at the 4-position of the pyrimidine ringor the 2-position of the pyridine ring, is defined as any salt, ester,acylhydrazide, imidate, thioimidate, amidine, amide, orthoester,acylcyanide, acyl halide, thioester, thionoester, dithiolester, nitrileor any other acid derivative well known in the art which (a) does notsubstantially affect the herbicidal activity of the active ingredient,i.e., the 2-(substituted)-6-amino-5-(alkyl, alkenyl oralkynyl)-4-pyrimidinecarboxylic acid or the6-(substituted)-4-amino-3-(alkyl, alkenyl or alkynyl) picolinic acid,and (b) is or can be hydrolyzed, oxidized or metabolized in plants orsoil to the 4-pyrimidinecarboxylic acid or the picolinic acid of FormulaIa that, depending upon the pH, is in the dissociated or theundissociated form. The preferred agriculturally acceptable derivativesof the carboxylic acid are agriculturally acceptable salts, esters andamides. Likewise, an “agriculturally acceptable derivative”, when usedto describe the amine functionality at the 6- or 4-position, is definedas any salt, silylamine, phosphorylamine, phosphinimine,phosphoramidate, sulfonamide, sulfilimine, sulfoximine, aminal,hemiaminal, amide, thioamide, carbamate, thiocarbamate, amidine, urea,imine, nitro, nitroso, azide, or any other nitrogen containingderivative well known in the art which (a) does not substantially affectthe herbicidal activity of the active ingredient, i.e., the2-(substituted)-6-amino-5-(alkyl, alkenyl oralkynyl)-4-pyrimidinecarboxylic acid or the6-(substituted)-4-amino-3-(alkyl, alkenyl or alkynyl) picolinic acid,and (b) is or can be hydrolyzed in plants or soil to a free amine.N-Oxides which are also capable of breaking into the parent pyrimidineor pyridine are also covered by the scope of this invention.

Suitable salts include those derived from alkali or alkaline earthmetals and those derived from ammonia and amines. Preferred cationsinclude sodium, potassium, magnesium, and aminium cations of theformula:R₈R₉R₁₀NH⁺wherein R₈, R₉ and R₁₀ each, independently represents hydrogen or C₁-C₁₂alkyl, C₃-C₁₂ alkenyl or C₃-C₁₂ alkynyl, each of which is optionallysubstituted by one or more hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio orphenyl groups, provided that R₈, R₉ and R₁₀ are sterically compatible.Additionally, any two of R₈, R₉ and R₁₀ together may represent analiphatic difunctional moiety containing 1 to 12 carbon atoms and up totwo oxygen or sulfur atoms. Salts of the compounds of Formula I can beprepared by treatment of compounds of Formula I with a metal hydroxide,such as sodium hydroxide, or an amine, such as ammonia, trimethylamine,diethanolamine, 2-methylthiopropylamine, bisallylamine,2-butoxyethyl-amine, morpholine, cyclododecylamine, or benzylamine.Amine salts are often preferred forms of the compounds of Formula Ibecause they are water-soluble and lend themselves to the preparation ofdesirable aqueous based herbicidal compositions.

Suitable esters include those derived from C₁-C₁₂ alkyl, C₃-C₁₂ alkenylor C₃-C₁₂ alkynyl alcohols, such as methanol, iso-propanol, butanol,2-ethylhexanol, butoxyethanol, methoxypropanol, allyl alcohol, propargylalcohol or cyclohexanol. Esters can be prepared by coupling of the4-pyrimidine carboxylic acids or picolinic acids with the alcohol usingany number of suitable activating agents such as those used for peptidecouplings such as dicyclohexylcarbodiimide (DCC) or carbonyl diimidazole(CDI), by reacting the corresponding acid chloride of a4-pyrimidinecarboxylic acid or picolinic acid of Formula I with anappropriate alcohol, by reacting the corresponding4-pyrimidinecarboxylic acid or picolinic acid of Formula I with anappropriate alcohol in the presence of an acid catalyst or bytransesterification. Suitable amides include those derived from ammoniaor from C₁-C₁₂ alkyl, C₃-C₁₂ alkenyl or C₃-C₁₂ alkynyl mono- ordi-substituted amines, such as but not limited to dimethylamine,diethanolamine, 2-methylthiopropylamine, bisallylamine,2-butoxyethylamine, cyclododecylamine, benzylamine or cyclic or aromaticamines with or without additional heteroatoms such as but not limited toaziridine, azetidine, pyrrolidine, pyrrole, imidazole, tetrazole ormorpholine. Amides can be prepared by reacting the corresponding4-pyrimidinecarboxylic acid or picolinic acid chloride, mixed anhydride,or carboxylic ester of Formula I with ammonia or an appropriate amine.

The terms “alkyl”, “alkenyl” and “alkynyl”, as well as derivative termssuch as “alkoxy”, “acyl”, “alkylthio” and “alkylsulfonyl”, as usedherein, include within their scope straight chain, branched chain andcyclic moieties. The terms “alkenyl” and “alkynyl” are intended toinclude one or more unsaturated bonds.

The term “aryl”, as well as derivative terms such as “aryloxy”, refersto a phenyl.

Unless specifically limited otherwise, the term “halogen” includingderivative terms such as “halo” refers to fluorine, chlorine, bromine,and iodine.

The terms “haloalkyl,” “haloalkoxy” and “haloalkylthio” refer to alkyland alkoxy groups substituted with from 1 to the maximum possible numberof halogen atoms.

The compounds of Formula I can be made using well-known chemicalprocedures. Many procedural details for making compounds of Formula Ican be found in the following patent applications: WO 2007/082076 A1; WO2005/063721 A1; U.S. Pat. Nos. 7,300,907 B2; 6,297,197 B1; 6,784,137 B2;7,314,849 B2; and US Patent Application Publication 2004/0198608 A1.Intermediates not specifically mentioned in the above patentapplications are either commercially available, can be made by routesdisclosed in the chemical literature, or can be readily synthesized fromcommercial starting materials utilizing standard procedures.

As shown in Scheme 1, many 2-(substituted)-6-amino-5-(alkyl, alkenyl oralkynyl)-4-pyrimidinecarboxylic acid esters or6-(substituted)-4-amino-3-(alkyl, alkenyl or alkynyl) picolinic acidesters of Formula I can be prepared by reaction of an appropriatelysubstituted 5-halopyrimidine or 3-halopyridine of Formula II and anorganometallic compound of type III in an inert solvent in the presenceof a transition metal catalyst.

In this case W can be N or CR₅; Q can be chlorine, bromine or iodine; R₁can be alkyl, haloalkyl, alkenyl, haloalkenyl, or alkynyl group; and Mcan be tri-(C₁-C₄ alkyl)tin or B(OR₁₁)(OR₁₂), where R₁₁ and R₁₂ areindependent of one another, hydrogen, C₁-C₆ alkyl, or when takentogether form an ethylene or propylene group; and “Catalyst” can be atransition metal catalyst, in particular a palladium catalyst such asbis(triphenylphosphine) palladium(II) dichloride. The method of Scheme 1is illustrated in Examples 17, 18, 21, 22, 24, 25, 27, 28, and 30.

As shown in Scheme 2, many2-(substituted)-6-amino-5-halo-4-pyrimidinecarboxylic acid esters ofFormula II can be made from compounds of Formula IV by reaction with ahalogenating reagent such as N-bromosuccinimide in a solvent such aschloroform or acetonitrile. In this case, Q can be chlorine, bromine oriodine. The method of Scheme 2 is illustrated in Example 16.

As shown in Scheme 3, many2-(substituted)-6-amino-4-pyrimidinecarboxylic acid esters of Formula Iand IV can be prepared by reaction of appropriately substituted2-chloropyrimidines of Formula V and VI and an organometallic compoundof type VII in an inert solvent in the presence of a transition metalcatalyst.

In this case R₁ can be an alkyl, haloalkyl, alkenyl, haloalkenyl, oralkynyl group; R₂ can be an alkyl, haloakyl, alkenyl, haloalkenyl oraryl group; M can be tri-(C₁-C₄ alkyl)tin or B(OR₁₁)(OR₁₂), where R₁₁and R₁₂ are independent of one another, hydrogen, C₁-C₆ alkyl, or whentaken together form an ethylene or propylene group; and “Catalyst” canbe a transition metal catalyst, in particular a palladium catalyst suchas bis(triphenylphosphine) palladium(II) dichloride. The methods ofScheme 3 are illustrated in Examples 15 and 19.

As shown in Scheme 4, many 2-chloro-6-amino-5-alkyl, alkenyl oralkynyl-4-pyrimidinecarboxylic acid esters of Formula V can be obtainedby reaction of appropriately substituted pyrimidines of Formula VIII andan organometallic compound of type III in an inert solvent in thepresence of a transition metal catalyst.

In this case R₁ can be an alkyl, haloalkyl, alkenyl, haloalkenyl oralkynyl group; M can be tri-(C₁-C₄ alkyl)tin or B(OR₁₁)(OR₁₂), where R₁₁and R₁₂ are independent of one another, hydrogen, C₁-C₆ alkyl, or whentaken together form an ethylene or propylene group; and “Catalyst” canbe a transition metal catalyst, in particular a palladium catalyst suchas bis(triphenylphosphine)-palladium(II) dichloride. The method ofScheme 4 is illustrated in Example 13.

As shown in Scheme 5, many2-chloro-6-amino-5-iodo-4-pyrimidinecarboxylic acid esters pyrimidinesof Formula VIII can be obtained by reaction of pyrimidines of Formula IXwith amines of type X. Pyrimidines of Formula IX can be prepared fromcompounds of Formula XI by reaction with reagents such as phosphorousoxychloride either neat or in the presence of a catalytic amount ofdimethylformamide. The methods of Scheme 5 are illustrated in Examples11 and 12.

It is recognized that some reagents and reaction conditions disclosedherein or in the chemical literature for preparing compounds of FormulaI may not be compatible with certain functionalities present in theintermediates. In these instances, the incorporation ofprotection/deprotection sequences or functional group interconversionsinto the synthesis will aid in obtaining the desired products. The useand choice of the protection groups will be apparent to one skilled inchemical synthesis.

One skilled in the art will recognize that, in some cases, after theintroduction of a given reagent as disclosed herein or in the chemicalliterature, it may be necessary to perform additional routine syntheticsteps not described in detail to complete the synthesis of compounds ofFormula I. One skilled in the art will also recognize that it maynecessary to perform a combination of the steps disclosed herein or inthe chemical literature in an order other than that implied by theparticular sequence presented to prepare the compounds of Formula I.

Finally, one skilled in the art will also recognize that compounds ofFormula I and the intermediates described herein or in the chemicalliterature can be subjected to various electrophilic, nucleophilic,radical, organometallic, oxidation, and reduction reactions to addsubstituents or modify existing substituents.

The compounds of Formula I have been found to be useful as pre-emergenceand post-emergence herbicides. They can be employed at non-selective(higher) rates of application to control a broad spectrum of thevegetation in an area or at lower rates of application for the selectivecontrol of undesirable vegetation. Areas of application include pastureand rangelands, roadsides and rights of way, power lines and anyindustrial areas, as well as turf and ornamental environments wherecontrol of undesirable vegetation is desirable. Another use is thecontrol of unwanted vegetation in crops such as corn, rice and cereals.They can also be used to control undesirable vegetation in tree cropssuch as citrus, apple, rubber, oil palm, forestry and others. It isusually preferred to employ the compounds postemergence. It is furtherusually preferred to use the compounds to control a wide spectrum ofwoody plants, broadleaf and grass weeds, and sedges. Use of thecompounds to control undesirable vegetation in established crops isespecially indicated. While each of the2-(substituted)-6-amino-5-(alkyl, alkenyl oralkynyl)-4-pyrimidinecarboxylate and 6-(substituted)-4-amino-3-(alkyl,alkenyl or alkynyl) picolinic compounds encompassed by Formula I iswithin the scope of the invention, the degree of herbicidal activity,the crop selectivity, and the spectrum of weed control obtained variesdepending upon the substituents present. An appropriate compound for anyspecific herbicidal utility can be identified by using the informationpresented herein and routine testing.

The term herbicide is used herein to mean an active ingredient thatkills, controls or otherwise adversely modifies the growth of plants. Anherbicidally effective or vegetation controlling amount is an amount ofactive ingredient which causes an adversely modifying effect andincludes deviations from natural development, killing, regulation,desiccation, retardation, and the like. The terms plants and vegetationinclude germinant seeds, emerging seedlings and established vegetation.

Herbicidal activity is exhibited by the compounds of the presentinvention when they are applied directly to the plant or to the locus ofthe plant at any stage of growth or before planting or emergence. Theeffect observed depends upon the plant species to be controlled, thestage of growth of the plant, the application parameters of dilution andspray drop size, the particle size of solid components, theenvironmental conditions at the time of use, the specific compoundemployed, the specific adjuvants and carriers employed, the soil type,and the like, as well as the amount of chemical applied. These and otherfactors can be adjusted as is known in the art to promote non-selectiveor selective herbicidal action. Generally, it is preferred to apply thecompounds of Formula I postemergence to relatively immature undesirablevegetation to achieve the maximum control of weeds.

Application rates of about 1 to about 1,000 g/Ha are generally employedin postemergence operations; for preemergence applications, rates ofabout 10 to about 2,000 g/Ha are generally employed. The higher ratesdesignated generally give non-selective control of a broad variety ofundesirable vegetation. The lower rates typically give selective controland can be employed in the locus of crops.

The herbicidal compounds of the present invention are often applied inconjunction with one or more other herbicides to control a wider varietyof undesirable vegetation. When used in conjunction with otherherbicides, the presently claimed compounds can be formulated with theother herbicide or herbicides, tank mixed with the other herbicide orherbicides or applied sequentially with the other herbicide orherbicides. Some of the herbicides that can be employed in conjunctionwith the compounds of the present invention include: amide herbicidessuch as allidochlor, beflubutamid, benzadox, benzipram, bromobutide,cafenstrole, CDEA, chlorthiamid, cyprazole, dimethenamid,dimethenamid-P, diphenamid, epronaz, etnipromid, fentrazamide, flupoxam,fomesafen, halosafen, isocarbamid, isoxaben, napropamide, naptalam,pethoxamid, propyzamide, quinonamid and tebutam; anilide herbicides suchas chloranocryl, cisanilide, clomeprop, cypromid, diflufenican,etobenzanid, fenasulam, flufenacet, flufenican, mefenacet, mefluidide,metamifop, monalide, naproanilide, pentanochlor, picolinafen andpropanil; arylalanine herbicides such as benzoylprop, flampropandflamprop-M; chloroacetanilide herbicides such as acetochlor, alachlor,butachlor, butenachlor, delachlor, diethatyl, dimethachlor, metazachlor,metolachlor, S-metolachlor, pretilachlor, propachlor, propisochlor,prynachlor, terbuchlor, thenylchlor and xylachlor; sulfonanilideherbicides such as benzofluor, perfluidone, pyrimisulfan and profluazol;sulfonamide herbicides such as asulam, carbasulam, fenasulam andoryzalin; antibiotic herbicides such as bilanafos; benzoic acidherbicides such as chloramben, dicamba, 2,3,6-TBA and tricamba;pyrimidinyloxybenzoic acid herbicides such as bispyribac andpyriminobac; pyrimidinylthiobenzoic acid herbicides such as pyrithiobac;phthalic acid herbicides such as chlorthal; picolinic acid herbicidessuch as aminopyralid, clopyralid and picloram; quinolinecarboxylic acidherbicides such as quinclorac and quinmerac; arsenical herbicides suchas cacodylic acid, CMA, DSMA, hexaflurate, MAA, MAMA, MSMA, potassiumarsenite and sodium arsenite; benzoylcyclohexanedione herbicides such asmesotrione, sulcotrione, tefuryltrione and tembotrione; benzofuranylalkylsulfonate herbicides such as benfuresate and ethofumesate;carbamate herbicides such as asulam, carboxazole chlorprocarb,dichlormate, fenasulam, karbutilate and terbucarb; carbanilateherbicides such as barban, BCPC, carbasulam, carbetamide, CEPC,chlorbufam, chlorpropham, CPPC, desmedipham, phenisopham, phenmedipham,phenmedipham-ethyl, propham and swep; cyclohexene oxime herbicides suchas alloxydim, butroxydim, clethodim, cloproxydim, cycloxydim,profoxydim, sethoxydim, tepraloxydim and tralkoxydim;cyclopropylisoxazole herbicides such as isoxachlortole and isoxaflutole;dicarboximide herbicides such as benzfendizone, cinidon-ethyl, flumezin,flumiclorac, flumioxazin and flumipropyn; dinitroaniline herbicides suchas benfluralin, butralin, dinitramine, ethalfluralin, fluchloralin,isopropalin, methalpropalin, nitralin, oryzalin, pendimethalin,prodiamine, profluralin and trifluralin; dinitrophenol herbicides suchas dinofenate, dinoprop, dinosam, dinoseb, dinoterb, DNOC, etinofen andmedinoterb; diphenyl ether herbicides such as ethoxyfen; nitrophenylether herbicides such as acifluorfen, aclonifen, bifenox,chlomethoxyfen, chlornitrofen, etnipromid, fluorodifen, fluoroglycofen,fluoronitrofen, fomesafen, furyloxyfen, halosafen, lactofen, nitrofen,nitrofluorfen and oxyfluorfen; dithiocarbamate herbicides such asdazomet and metam; halogenated aliphatic herbicides such as alorac,chloropon, dalapon, flupropanate, hexachloroacetone, iodomethane, methylbromide, monochloroacetic acid, SMA and TCA; imidazolinone herbicidessuch as imazamethabenz, imazamox, imazapic, imazapyr, imazaquin andimazethapyr; inorganic herbicides such as ammonium sulfamate, borax,calcium chlorate, copper sulfate, ferrous sulfate, potassium azide,potassium cyanate, sodium azide, sodium chlorate and sulfuric acid;nitrile herbicides such as bromobonil, bromoxynil, chloroxynil,dichlobenil, iodobonil, ioxynil and pyraclonil; organophosphorusherbicides such as amiprofos-methyl, anilofos, bensulide, bilanafos,butamifos, 2,4-DEP, DMPA, EBEP, fosamine, glufosinate, glyphosate andpiperophos; phenoxy herbicides such as bromofenoxim, clomeprop, 2,4-DEB,2,4-DEP, difenopenten, disul, erbon, etnipromid, fenteracol andtrifopsime; phenoxyacetic herbicides such as 4-CPA, 2,4-D, 3,4-DA, MCPA,MCPA-thioethyl and 2,4,5-T; phenoxybutyric herbicides such as 4-CPB,2,4-DB, 3,4-DB, MCPB and 2,4,5-TB; phenoxypropionic herbicides such ascloprop, 4-CPP, dichlorprop, dichlorprop-P, 3,4-DP, fenoprop,mecopropand mecoprop-P; aryloxyphenoxypropionic herbicides such aschlorazifop, clodinafop, clofop, cyhalofop, diclofop, fenoxaprop,fenoxaprop-P, fenthiaprop, fluazifop, fluazifop-P, haloxyfop,haloxyfop-P, isoxapyrifop, metamifop, propaquizafop, quizalofop,quizalofop-P and trifop; phenylenediamine herbicides such as dinitramineand prodiamine; pyrazolyl herbicides such as benzofenap, pyrazolynate,pyrasulfotole, pyrazoxyfen, pyroxasulfone and topramezone;pyrazolylphenyl herbicides such as fluazolate and pyraflufen; pyridazineherbicides such as credazine, pyridafol and pyridate; pyridazinoneherbicides such as brompyrazon, chloridazon, dimidazon, flufenpyr,metflurazon, norflurazon, oxapyrazon and pydanon; pyridine herbicidessuch as aminopyralid, cliodinate, clopyralid, dithiopyr, fluoroxypyr,haloxydine, picloram, picolinafen, pyriclor, thiazopyr and triclopyr;pyrimidinediamine herbicides such as iprymidam and tioclorim; quaternaryammonium herbicides such as cyperquat, diethamquat, difenzoquat, diquat,morfamquat and paraquat; thiocarbamate herbicides such as butylate,cycloate, di-allate, EPTC, esprocarb, ethiolate, isopolinate,methiobencarb, molinate, orbencarb, pebulate, prosulfocarb,pyributicarb, sulfallate, thiobencarb, tiocarbazil, tri-allate andvernolate; thiocarbonate herbicides such as dimexano, EXD and proxan;thiourea herbicides such as methiuron; triazine herbicides such asdipropetryn, triaziflam and trihydroxytriazine; chlorotriazineherbicides such as atrazine, chlorazine, cyanazine, cyprazine,eglinazine, ipazine, mesoprazine, procyazine, proglinazine, propazine,sebuthylazine, simazine, terbuthylazine and trietazine; methoxytriazineherbicides such as atraton, methometon, prometon, secbumeton, simetonand terbumeton; methylthiotriazine herbicides such as ametryn,aziprotryne, cyanatryn, desmetryn, dimethametryn, methoprotryne,prometryn, simetryn and terbutryn; triazinone herbicides such asametridione, amibuzin, hexazinone, isomethiozin, metamitron andmetribuzin; triazole herbicides such as amitrole, cafenstrole, epronazand flupoxam; triazolone herbicides such as amicarbazone, bencarbazone,carfentrazone, flucarbazone, propoxycarbazone, sulfentrazone andthiencarbazone-methyl; triazolopyrimidine herbicides such ascloransulam, diclosulam, florasulam, flumetsulam, metosulam, penoxsulamand pyroxsulam; uracil herbicides such as butafenacil, bromacil,flupropacil, isocil, lenacil and terbacil; 3-phenyluracils; ureaherbicides such as benzthiazuron, cumyluron, cycluron, dichloralurea,diflufenzopyr, isonoruron, isouron, methabenzthiazuron, monisouron andnoruron; phenylurea herbicides such as anisuron, buturon, chlorbromuron,chloreturon, chlorotoluron, chloroxuron, daimuron, difenoxuron,dimefuron, diuron, fenuron, fluometuron, fluothiuron, isoproturon,linuron, methiuron, methyldymron, metobenzuron, metobromuron, metoxuron,monolinuron, monuron, neburon, parafluoron, phenobenzuron, siduron,tetrafluoron and thidiazuron; pyrimidinylsulfonylurea herbicides such asamidosulfuron, azimsulfuron, bensulfuron, chlorimuron, cyclosulfamuron,ethoxysulfuron, flazasulfuron, flucetosulfuron, flupyrsulfuron,foramsulfuron, halosulfuron, imazosulfuron, mesosulfuron, nicosulfuron,orthosulfamuron, oxasulfuron, primisulfuron, pyrazosulfuron,rimsulfuron, sulfometuron, sulfosulfuron and trifloxysulfuron;triazinylsulfonylurea herbicides such as chlorsulfuron, cinosulfuron,ethametsulfuron, iodosulfuron, metsulfuron, prosulfuron, thifensulfuron,triasulfuron, tribenuron, triflusulfuron and tritosulfuron;thiadiazolylurea herbicides such as buthiuron, ethidimuron, tebuthiuron,thiazafluoron and thidiazuron; and unclassified herbicides such asacrolein, allyl alcohol, azafenidin, benazolin, bentazone,benzobicyclon, buthidazole, calcium cyanamide, cambendichlor,chlorfenac, chlorfenprop, chlorflurazole, chlorflurenol, cinmethylin,clomazone, CPMF, cresol, ortho-dichlorobenzene, dimepiperate, endothal,fluoromidine, fluridone, fluorochloridone, flurtamone, fluthiacet,indanofan, methazole, methyl isothiocyanate, nipyraclofen, OCH,oxadiargyl, oxadiazon, oxaziclomefone, pentachlorophenol, pentoxazone,phenylmercury acetate, pinoxaden, prosulfalin, pyribenzoxim, pyriftalid,quinoclamine, rhodethanil, sulglycapin, thidiazimin, tridiphane,trimeturon, tripropindan and tritac. The herbicidal compounds of thepresent invention can, further, be used in conjunction with glyphosate,glufosinate, dicamba, imidazolinones or 2,4-D on glyphosate-tolerant,glufosinate-tolerant, dicamba-tolerant, imidazolinone-tolerant or2,4-D-tolerant crops. It is generally preferred to use the compounds ofthe invention in combination with herbicides that are selective for thecrop being treated and which complement the spectrum of weeds controlledby these compounds at the application rate employed. It is furthergenerally preferred to apply the compounds of the invention and othercomplementary herbicides at the same time, either as a combinationformulation or as a tank mix.

The compounds of the present invention can generally be employed incombination with known herbicide safeners, such as benoxacor,benthiocarb, brassinolide, cloquintocet (mexyl), cyometrinil, daimuron,dichlormid, dicyclonon, dimepiperate, disulfoton, fenchlorazole-ethyl,fenclorim, flurazole, fluxofenim, furilazole, isoxadifen-ethyl,mefenpyr-diethyl, MG 191, MON 4660, naphthalic anhydride (NA),oxabetrinil, R29148 and N-phenyl-sulfonylbenzoic acid amides, to enhancetheir selectivity. They can additionally be employed to controlundesirable vegetation in many crops that have been made tolerant to orresistant to them or to other herbicides by genetic manipulation or bymutation and selection. For example, corn, wheat, rice, soybean,sugarbeet, cotton, canola, and other crops that have been made tolerantor resistant to compounds that are acetolactate synthase inhibitors insensitive plants can be treated. Many glyphosate and glufosinatetolerant crops can be treated as well, alone or in combination withthese herbicides. Some crops (e.g. cotton) have been made tolerant toauxinic herbicides such as 2,4-dichlorophenoxyacetic acid. Theseherbicides may be used to treat such resistant crops or other auxintolerant crops.

While it is possible to utilize the 2-(substituted)-6-amino-5-(alkyl,alkenyl or alkynyl)-4-pyrimidinecarboxylate and6-(substituted)-4-amino-3-(alkyl, alkenyl or alkynyl) picolinatecompounds of Formula I directly as herbicides, it is preferable to usethem in mixtures containing an herbicidally effective amount of thecompound along with at least one agriculturally acceptable adjuvant orcarrier. Suitable adjuvants or carriers should not be phytotoxic tovaluable crops, particularly at the concentrations employed in applyingthe compositions for selective weed control in the presence of crops,and should not react chemically with the compounds of Formula I or othercomposition ingredients. Such mixtures can be designed for applicationdirectly to weeds or their locus or can be concentrates or formulationsthat are normally diluted with additional carriers and adjuvants beforeapplication. They can be solids, such as, for example, dusts, granules,water dispersible granules, or wettable powders, or liquids, such as,for example, emulsifiable concentrates, solutions, emulsions orsuspensions.

Suitable agricultural adjuvants and carriers that are useful inpreparing the herbicidal mixtures of the invention are well known tothose skilled in the art.

Liquid carriers that can be employed include water, toluene, xylene,petroleum naphtha, crop oil, acetone, methyl ethyl ketone,cyclohexanone, trichloroethylene, perchloroethylene, ethyl acetate, amylacetate, butyl acetate, propylene glycol monomethyl ether and diethyleneglycol monomethyl ether, methanol, ethanol, isopropanol, amyl alcohol,ethylene glycol, propylene glycol, glycerine, N-methyl-2-pyrrolidinone,N,N-dimethyl alkylamides, dimethyl sulfoxide, liquid fertilizers and thelike. Water is generally the carrier of choice for the dilution ofconcentrates.

Suitable solid carriers include talc, pyrophyllite clay, silica,attapulgus clay, kaolin clay, kieselguhr, chalk, diatomaceous earth,lime, calcium carbonate, bentonite clay, Fuller's earth, cotton seedhulls, wheat flour, soybean flour, pumice, wood flour, walnut shellflour, lignin, and the like.

It is usually desirable to incorporate one or more surface-active agentsinto the compositions of the present invention. Such surface-activeagents are advantageously employed in both solid and liquidcompositions, especially those designed to be diluted with carrierbefore application. The surface-active agents can be anionic, cationicor nonionic in character and can be employed as emulsifying agents,wetting agents, suspending agents, or for other purposes. Typicalsurface-active agents include salts of alkyl sulfates, such asdiethanolammonium lauryl sulfate; alkylarylsulfonate salts, such ascalcium dodecylbenzene-sulfonate; alkylphenol-alkylene oxide additionproducts, such as nonylphenol-C₁₈ ethoxylate; alcohol-alkylene oxideaddition products, such as tridecyl alcohol-C₁₆ ethoxylate; soaps, suchas sodium stearate; alkylnaphthalene-sulfonate salts, such as sodiumdibutyl-naphthalenesulfonate; dialkyl esters of sulfosuccinate salts,such as sodium di(2-ethylhexyl) sulfosuccinate; sorbitol esters, such assorbitol oleate; quaternary amines, such as lauryl trimethylammoniumchloride; polyethylene glycol esters of fatty acids, such aspolyethylene glycol stearate; block copolymers of ethylene oxide andpropylene oxide; and salts of mono and dialkyl phosphate esters.

Other adjuvants commonly used in agricultural compositions includecompatibilizing agents, antifoam agents, sequestering agents,neutralizing agents and buffers, corrosion inhibitors, dyes, odorants,spreading agents, penetration aids, sticking agents, dispersing agents,thickening agents, freezing point depressants, antimicrobial agents, andthe like. The compositions may also contain other compatible components,for example, other herbicides, plant growth regulants, fungicides,insecticides, and the like and can be form-ulated with liquidfertilizers or solid, particulate fertilizer carriers such as ammoniumnitrate, urea and the like.

The concentration of the active ingredients in the herbicidalcompositions of this invention is generally from about 0.001 to about 98percent by weight. Concentrations from about 0.01 to about 90 percent byweight are often employed. In compositions designed to be employed asconcentrates, the active ingredient is generally present in aconcentration from about 5 to about 98 weight percent, preferably about10 to about 90 weight percent. Such compositions are typically dilutedwith an inert carrier, such as water, before application. The dilutedcompositions usually applied to weeds or the locus of weeds generallycontain about 0.0001 to about 1 weight percent active ingredient andpreferably contain about 0.001 to about 0.05 weight percent.

The present compositions can be applied to weeds or their locus by theuse of conventional ground or aerial dusters, sprayers, and granuleapplicators, diffusion in standing water, by addition to irrigationwater, and by other conventional means known to those skilled in theart.

The following Examples are presented to illustrate the various aspectsof this invention and should not be construed as limitations to theclaims.

EXAMPLES 1. Preparation of 4-Chloro-2,5-difluorophenylamine

Tin (II) chloride dihydrate (15.5 g, 68.7 mmol) was dissolved in ethylacetate (50 mL) and 1-chloro-2,5-difluoro-4-nitrobenzene (2.65 g, 13.7mmol) was added dropwise. The reaction mixture was then stirred at 70°C. for 1 h. The reaction mixture was then carefully added to saturatedaqueous sodium bicarbonate and extracted with ethyl acetate. The organicphase was washed several more times with water, dried, filtered,concentrated and purified by flash chromatography on silica gel(hexane/diethyl ether) to give the title compound as a white solid (1.65g, 73.9% yield): ¹H NMR (CDCl₃) δ 7.02 (dd, 1H), 6.57 (dd, 1H), 3.81 (brs, 2H).

2. Preparation of 1-Bromo-4-chloro-2,5-difluorobenzene

Anhydrous copper (II) bromide (2.7 g, 12.1 mmol) and t-butyl nitrite(1.56 g, 15.1 mmol) were combined in anhydrous acetonitrile (25 mL). Theresulting mixture was heated to 65° C. and a solution of4-chloro-2,5-difluoro-phenylamine (1.65 g, 10.1 mmol) in anhydrousacetonitrile (2 mL) was added dropwise (vigorous gas evolution wasnoted). After the reaction mixture cooled to ambient temperature, it wasadded to 2N HCl and extracted twice with diethyl ether. The organicextracts were then combined, washed with 2N HCl, washed with saturatedsodium bicarbonate, dried, concentrated and purified by flashchromatography on silica gel (hexanes) to give the title compound as awhite solid (1.11 g, 48.4% yield): ¹H NMR (CDCl₃) δ 7.38 (dd, 2H), 7.21(dd, 2H).

3. Preparation of2-(4-Chloro-2,5-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

1-Bromo-4-chloro-2,5-difluorobenzene (1.11 g, 4.9 mmol) was dissolved intetrahydrofuran (THF; 15 mL) and cooled to −10° C. A 2.0M solution ofisopropyl-magnesium chloride (2.7 mL, 5.4 mmol) in THF was addeddropwise via syringe. The reaction mixture was stirred at −10° C. for 1h, allowed to warm toward 0° C. for 1 h, then cooled again to −10° C. Asolution of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.0 g,5.4 mmol) in THF (1.0 mL) was then added dropwise and the reactionmixture was allowed to warm to ambient temperature. The reaction mixturewas then added to diethyl ether and extracted with 1N sodium hydroxidetwice. The aqueous phases were combined, acidified to pH 3 withconcentrated HCl, and extracted with dichloromethane twice. The organicphases were combined, dried, filtered and concentrated to give the titlecompound (0.97 g, 72.3% yield) that was used without furtherpurification: ¹H NMR (CDCl₃) δ 7.45 (dd, 1H), 7.09 dd, 1H), 1.36 (s,12H).

Another compound prepared by the procedure of Example 3 is:

2-(4-Chloro-2-fluoro-5-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane:¹H NMR (CDCl₃) δ 7.58 (d, 1H), 7.03 (d, 1H), 2.32 (s, 3H), 1.35 (s,12H).

4. Preparation of 1-(5-Bromo-2-chlorophenyl)-ethanol

Sodium borohydride (1.182 g, 51.4 mmol) was added to a stirred solutionof 1-(5-bromo-2-chlorophenyl)ethanone (10 g, 42.8 mmol) in methanol at0° C. The resulting bubbling white mixture was allowed to warm toambient temperature and stirred for 2 h. The reaction mixture wasquenched with acetone (50 mL) and concentrated by rotary evaporation.The residue was partitioned between ethyl acetate and water. The organicphase was dried and concentrated to yield the title compound (10 g, 99%yield) as a white solid: ¹H NMR (CDCl₃) δ 7.75 (d, 1H), 7.32 (m, 1H),7.19 (m, 1H), 5.23 (q, 1H), 1.95 (d, 1H), 1.48 (d, 3H).

Another compound prepared by the procedure of Example 4 is:

1-(2-Chloro-6-fluorophenyl)ethanol: ¹H NMR (300 MHz, CDCl₃) δ 7.14-7.22(m, 2H), 6.99 (m, 1H), 5.38 (m, 1H), 2.48 (m, 1H), 1.63 (dd, 3H, J=1, 7Hz).

5. Preparation of 4-Bromo-1-chloro-2-(1-fluoroethyl)-benzene

Bis(2-methoxyethyl)aminosulfur trifluoride (4.5 g, 20.34 mmol) was addedto a stirred solution of 1-(5-bromo-2-chlorophenyl)ethanol (3.99 g,16.95 mmol) in dichloromethane (50 mL) at 0° C. The resulting solutionwas stirred at 0° C. for 3 h. The reaction mixture was quenched with a5% solution of aqueous sodium bicarbonate (100 mL) and the resultingbubbling biphasic reaction mixture was vigorously stirred at 0° C. for15 min. The reaction mixture was diluted with water (50 mL) andextracted with dichloromethane twice. The combined organic layers werewashed with 1M hydrochloric acid, dried and concentrated by rotaryevaporation. The product was purified by flash chromatography on silicagel (hexanes) to yield the title compound (2.65 g, 11.16 mmol, 65.8%yield) as a clear oil: ¹H NMR (CDCl₃) δ 7.65 (d, 1H), 7.37 (m, 1H), 7.20(m, 1H), 5.88 (dq, 1H), 1.61 (dd, 3H).

Another compound prepared by the procedure of Example 5 is:

1-Chloro-3-fluoro-2-(1-fluoroethyl)benzene: ¹H NMR (300 MHz, CDCl₃) δ7.15-7.26 (m, 2H), 7.02 (m, 1H), 6.12 (dq, 1H, J=6, 46 Hz), 1.76 (ddd,3H, J=1, 7, 23 Hz).

6. Preparation of 1-Chloro-2-difluoromethoxy-3-fluorobenzene

2-Chloro-6-fluorophenol (1.8 g, 12.33 mmol) was dissolved indimethylformamide (DMF; 22 mL) and water (2.2 mL). Potassium carbonate(2.55 g, 18.5 mmol) and sodium chlorodifluoroacetate (4.7 g, 30.8 mmol)were then added and the solution was heated to 100° C. for 3 h. Thecooled reaction mixture was then diluted with concentrated HCl (10 mL)and the resulting solution was stirred for 2 h. The reaction mixture wasdiluted with diethyl ether, washed with water, washed twice with 1MNaOH, washed once with brine, dried, filtered and concentrated undervacuum to yield the title compound (1 g, 41% yield) that was used insubsequent reactions without further purification.

7. Preparation of2-[4-Chloro-3-(1-fluoroethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

4-Bromo-1-chloro-2-(1-fluoroethyl)benzene (2.55 g, 10.74 mmol) wasdissolved in dry diethyl ether (50 mL) and cooled to −75° C.n-Butyllithium (4.72 mL, 11.81 mmol) was added dropwise keeping thetemperature below −70° C. The reaction mixture was then stirred for 15min, then 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.197 g,11.81 mmol) was added and the reaction mixture was allowed to warm toambient temperature. The reaction mixture was then diluted with waterand diethyl ether. The aqueous phase was acidified with 12N HCl and theproduct was then extracted with diethyl ether. The organic phase wasdried and concentrated under vacuum to yield the title compound (1.55 g,5.45 mmol, 50.7% yield) as a white solid: ¹H NMR (CDCl₃) δ 7.94 (d, 1H),7.65 (m, 1H), 7.36 (m, 1H), 5.96 (dq, 1H), 1.64 (dd, 3H), 1.34 (s, 12H).

Another compound prepared by the procedure of Example 7 is:

[6-Chloro-2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-dimethylamine:¹H NMR (CDCl₃) δ 7.35 (m, 1H), 7.13 (m, 1H), 2.85 (d, 6H), 1.36 (s,12H).

8. Preparation of2-(4-Chloro-2,3-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

A 2.5M solution of n-butyllithium (2.69 ml, 6.73 mmol) in hexanes wasadded dropwise to a solution of 1-chloro-2,3-difluorobenzene (1 g, 6.73mmol) in THF (25 mL) cooled to −78° C. After 45 min at −78° C.,2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.253 g, 6.73mmol) was added dropwise after which the reaction mixture was allowed towarm to ambient temperature. The reaction mixture was diluted with waterand ethyl acetate, and the organic phase was extracted twice with water.The aqueous extracts were combined, acidified with 12N HCl to pH 3, andextracted with ethyl acetate. The organic extract was dried andconcentrated under vacuum to yield the title compound as an oil product(0.93 g, 50% yield): ¹H NMR (CDCl₃) δ 7.42 (m, 1H), 7.17 (m, 1H), 1.37(s, 12H).

Another compound prepared by the procedure of Example 8 is:

2-(4-Chloro-3-difluoromethoxy-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane:¹H NMR (CDCl₃) δ 7.1 (m, 1H), 7.02 (m, 1H), 6.8 (t, 1H), 1.23 (s, 12H).

9. Preparation of2-(4-Chloro-2-fluoro-3-(1-fluoroethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

A 2.5M solution of n-butyllithium (13 mL, 33 mmol) was added to astirred solution of diisopropylamine (5.0 mL, 35 mmol) in THF (50 mL) at−78° C. The resulting colorless solution was stirred at −78° C. for 20min, warmed to 0° C. for 20 min, and then cooled back to −78° C. for 20min A solution of 1-chloro-3-fluoro-2-(1-fluoroethyl)benzene (4.8 g, 27mmol, 1.0 equiv) in THF (20 mL) at −78° C. was transferred to the basesolution via cannula. The resulting dark brown solution was stirred at−78° C. for 2 h. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(8.3 mL, 41 mmol, 1.5 equiv) was added and the brown solution was slowlywarmed to 23° C. over 20 h. The reaction mixture was diluted with 0.1Mhydrochloric acid (300 mL) and extracted with dichloromethane thrice.The combined organic extracts were dried, filtered and concentrated byrotary evaporation to afford the title compound as a brown oil thatsolidified into a semi-solid upon standing (7.7 g, 94% yield). ¹H NMR(300 MHz, CDCl₃) δ 7.62 (m, 1H), 7.17 (m, 1H), 6.13 (dq, 1H, J=6, 46Hz), 1.75 (ddd, 3H, J=1, 7, 23 Hz), 1.36 (s, 12 H).

10. Preparation of5-Iodo-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid methylester

Methyl orotate (20.0 g, 118 mmol) was combined with iodine (12.8 g, 50mmol) and periodic acid (4.8 g, 21 mmol) in methanol (250 mL) and heatedat reflux for 20 h. After cooling to ambient temperature, the volatileswere removed by rotary evaporation. The solid residue was slurried inwater, collected by filtration, washed well with water and dried undervacuum at 70° C. to provide the title compound (34 g, 97% yield) as asolid. It was used without further purification. MS: m/z=296.

11. Preparation of 2,6-Dichloro-5-iodopyrimidine-4-carboxylic acidmethyl ester

5-Iodo-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid methylester (5.0 g, 17 mmol) was added to POCl₃ (30 mL), treated with 0.5 mLDMF and heated to reflux for 3 h. The excess POCl₃ was removed undervacuum and the residue was stirred with ice and extracted withdichloromethane. The dichloromethane extract was washed with water,dried and evaporated. The residue was chromatographed on silica (5-15%ethyl acetate/hexane) to give the title compound (2.7 g, 48% yield). MS:m/z=332.

12. Preparation of 6-Amino-2-chloro-5-iodopyrimidine-4-carboxylic acidmethyl ester

2,6-Dichloro-5-iodopyrimidine-4-carboxylic acid methyl ester (12 g, 36mmol) was dissolved in dry dimethyl sulfoxide (DMSO; 100 mL) and treatedwith a stream of ammonia at such a rate when combined with externalwater bath cooling to keep the temperature in the range of 20-30° C.After 90 min, the ammonia addition was complete and excess ammonia wasremoved from the mixture by sparging with a stream of nitrogen for 20min. The mixture was poured into water (200 mL) with stirring and theprecipitated product was extracted with ethyl acetate (75 mL) twice. Thecombined ethyl acetate extracts were washed twice with water (50 mL),once with saturated NaCl solution, dried and evaporated to give thetitle compound (10 g, 89% yield) that was used without furtherpurification. MS: M/Z=313.

13. Preparation of 6-Amino-2-chloro-5-vinylpyrimidine-4-carboxylic acidmethyl ester

6-Amino-2-chloro-5-iodopyrimidine-4-carboxylic acid methyl ester (10 g,32 mmol) was dissolved in 1,2-dichloroethane (100 mL), treated withvinyltributylstannane (11.6 mL, 12.6 g, 40 mmol) and sparged with anitrogen stream for 10 min. Bis(triphenylphosphine)palladium(II)dichloride (1.1 g, 1.6 mmol, 5 mole %) was added and the mixture washeated at reflux under a nitrogen atmosphere for 3 h. The mixture wascooled, stirred with 10% aqueous KHF₂ for 30 min, and filtered throughdiatomaceous earth to remove solids. The filter cake was washed withmore 1,2-dichloroethane and ethyl acetate. The combined filtrates werewashed with water, washed with saturated NaHCO₃, washed with brine,dried, and evaporated. The crude material was chromatographed on silica(5-20% ethyl acetate/dichloromethane containing 2% acetic acid) to givethe title compound (4.5 g, 70% yield). This material containedapproximately 5% PPh₃, but was used without further purification. MS:m/z=213. ¹H NMR(CDCl₃) δ 6.77(dd, 1H), 6.4(br, 2H), 5.70(d, 1H), 5.61(d,1H).

14. Preparation of 6-Amino-2-chloropyrimidine-4-carboxylic acid methylester

Ammonia was slowly bubbled through a solution of2,6-dichloro-pyrimidine-4-carboxylic acid methyl ester (20.0 g, 97 mmol,see H. Gershon, J. Org. Chem. 1962, 27, 3507-3510 for preparation) inDMSO (100 mL) cooled with an ice bath to maintain the temperature below70° C. When the temperature of the reaction solution began to decline,no additional ammonia was added. When the temperature of the reactionsolution reached 44° C., the ice bath was removed. When the temperatureof the reaction solution reached 32° C., the reaction mixture wasdiluted with 200 mL of water and filtered. The filtered product waswashed with water, washed with ethyl acetate, and dried under vacuum toprovide the title compound (14.4 g, 79% yield) that was used withoutfurther purification. Flash chromatography on silica gel yielded ananalytically pure sample of the title compound: ¹H NMR (DMSO-d₆) δ 7.7(br s, 2H), 7.00 (s, 1H), 3.84 (s, 3H).

15. Preparation of6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-pyrimidine-4-carboxylicacid methyl ester

6-Amino-2-chloropyrimidine-4-carboxylic acid methyl ester (2.25 g, 12mmol, 4-chloro-2-fluoro-3-methoxyphenylboronic acid (3.27 g, 16 mmol),and bis(triphenylphosphine)palladium(II) dichloride (842 mg, 1.2 mmol)were combined in 12 mL of 1,2-dimethoxyethane and 12 mL of water. Thereaction mixture was heated at 80° C. for 2 h and the cooled reactionmixture was partitioned between ethyl acetate and water. The organicphase was washed with water, dried, and concentrated under vacuum. Theproduct was purified by flash chromatography on silica gel to yield thetitle compound (2.0 g, 53.5% yield): mp 188-190° C.: ¹H NMR (CDCl₃) δ7.66 (dd, 1H), 7.22 (dd, 1H), 7.14 (s, 1H), 5.25 (br s, 2H), 4.0 (s,3H), 3.99 (s, 3H).

Other compounds prepared by the method of Example 15 include:

-   6-Amino-2-(4-chloro-2-fluorophenyl)pyrimidine-4-carboxylic acid    methyl ester: mp 192-194° C.-   6-Amino-2-(4-chlorophenyl)pyrimidine-4-carboxylic acid methyl ester:    mp decompose above 195° C.-   6-Amino-2-(4-chloro-3-methoxyphenyl)pyrimidine-4-carboxylic acid    methyl ester: mp 210-213° C.-   6-Amino-2-(4-chloro-2-fluoro-5-methoxyphenyl)pyrimidine-4-carboxylic    acid methyl ester: mp 218-220° C.

16. Preparation of6-Amino-5-bromo-2-(4-chloro-2-fluoro-3-methoxyphenyl)-pyrimidine-4-carboxylicacid methyl ester

6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)pyrimidine-4-carboxylicacid methyl ester (778 mg, 2.5 mmol) and N-bromosuccinimide (489 mg,2.75 mmol) were combined in chloroform (10 mL) and heated at reflux for12 h. The cooled reaction mixture was concentrated and the product waspurified by flash chromatography on silica gel to yield the titlecompound (752 mg, 77% yield): mp 173-175° C.: ¹H NMR (CDCl₃) δ 7.66 (dd,1H), 7.24 (dd, 1H), 5.73 (br s, 2H), 4.03 (s, 3H), 4.01 (d, 3H).

Other compounds prepared by the method of Example 16 include:

-   6-Amino-5-bromo-2-(4-chloro-2-fluorophenyl)pyrimidine-4-carboxylic    acid methyl ester: mp 186-188° C.-   6-Amino-5-bromo-2-(4-chlorophenyl)pyrimidine-4-carboxylic acid    methyl ester: mp: decompose above 154° C.-   6-Amino-5-bromo-2-(4-chloro-3-methoxyphenyl)pyrimidine-4-carboxylic    acid methyl ester: mp 146-151° C.-   6-Amino-5-bromo-2-(4-chloro-2-fluoro-5-methoxyphenyl)pyrimidine-4-carboxylic    acid methyl ester: mp 197-200° C.

17. Preparation of 6-Amino-2-cyclopropyl-5-methylpyrimidine-4-carboxylicacid ethyl ester (Compound 1)

6-Amino-5-bromo-2-cyclopropylpyrimidine-4-carboxylic acid ethyl ester(300 mg, 1.05 mmol; see WO 2005/063721 A1 for preparation),tetramethyltin (937 mg, 5.24 mmol), andbis(triphenylphosphine)palladium(II) dichloride (74 mg, 0.105 mmol) werecombined in 5 mL of 1,2-dichloroethane and heated in a CEM microwavereactor at 150° C. for 20 min. The resulting reaction mixture wasfiltered and concentrated. The product was purified by flashchromatography on silica gel (ethyl acetate/hexane gradient) followed bya purification by reverse phase chromatography to yield the titlecompound (116 mg, 50% yield): mp 130-132° C.: ¹H NMR (DMSO-d₆) δ 6.85(br s, 2H), 4.27 (q, 2H), 1.94 (s, 3H), 1.87 (m, 1H), 1.28 (t, 3H), 0.84(d, 4H).

Another compound prepared by the method of Example 17 is:

6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-methylpyrimidine-4-carboxylicacid methyl ester (Compound 2): mp 168-170° C.: ¹H NMR (CDCl₃) δ 7.60(m, 1H), 7.21 (m, 1H), 5.21 (br s, 2H), 3.99 (d, 3H), 3.98 (s, 3H), 2.29(s, 3H).

18. Preparation of6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-vinylpyrimidine-4-carboxylicacid methyl ester (Compound 3)

6-Amino-5-bromo-2-(4-chloro-2-fluoro-3-methoxyphenyl)-pyrimidine-4-carboxylicacid methyl ester (1.5 g, 3.84 mmol), tributyl(vinyl)tin (2.436 g, 7.68mmol), bis(triphenylphosphine)palladium(II) dichloride (0.270 g, 0.384mmol) were combined in 1,2-dichloroethane (4 mL) and heated at 130° C.for 15 min in a CEM microwave reactor. The cooled reaction mixture wasconcentrated onto silica gel and purified by flash chromatography onsilica gel (ethyl acetate/hexane gradient) to yield the title compound(1.06 g, 82% yield): mp 145-147° C.: ¹H NMR (CDCl₃) δ 7.64 (m, 1H), 7.22(m, 1H), 6.84 (dd, 1H), 5.68 (m, 2H), 5.43 (br s, 2H), 3.99 (d, 3H),3.95 (s, 3H).

Other compounds prepared by the method of Example 18 include:

6-Amino-2-cyclopropyl-5-vinylpyrimidine-4-carboxylic acid ethyl ester(Compound 4): mp 155-157° C.: ¹H NMR (CDCl₃) δ 6.69 (dd, 1H), 5.57 (dd,1H), 5.52 (dd, 1H), 5.13 (br s, 1H), 4.39 (1, 2H), 2.07 (m, 1H), 1.38(t, 3H), 1.07 (m, 2H), 0.96 (m, 1H).

6-Amino-2-(4-chloro-2-fluorophenyl)-5-vinylpyrimidine-4-carboxylic acidmethyl ester (Compound 5): mp 137-139° C.: ¹H NMR (CDCl₃) δ 7.96 (m,1H), 7.20 (m, 2H), 6.83 (dd, 1H), 5.67 (m, 2H), 5.42 (br s, 2H), 3.95(s, 3H).

6-Amino-2-(4-chlorophenyl)-5-vinylpyrimidine-4-carboxylic acid methylester (Compound 6): mp 164-167° C.: ¹H NMR (CDCl₃) δ 8.3 (m, 2H), 7.40(m, 2H), 6.80 (m, 1H), 5.6 (m, 2H), 5.37 (br s, 2H), 3.96 (s, 3H).

6-Amino-2-(4-chloro-3-methoxyphenyl)-5-vinylpyrimidine-4-carboxylic acidmethyl ester (Compound 7): mp 144-148° C.: ¹H NMR (CDCl₃) δ 7.92 (m,2H), 7.40 (d, 1H), 6.78 (m, 1H), 5.6 (m, 2H), 5.39 (br s, 1H), 4.01 (s,3H), 3.96 (s, 3H).

6-Amino-2-(4-chloro-2-fluoro-5-methoxyphenyl)-5-vinylpyrimidine-4-carboxylicacid methyl ester (Compound 8): mp 161-164° C.; ¹H NMR (DMSO-d₆) δ 7.52(m, 2H), 6.65 (m, 1H), 5.50 (m, 2H), 3.88 (s, 3H), 3.81 (s, 3H).

6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-(1-fluorovinyl)pyrimidine-4-carboxylic acid methyl ester (utilizedtributyl-(1-fluorovinyl)stannane prepared according to the proceduresfound in Bull. Chem. Soc. Jpn. 2002, 75(11), 2497-2502) (Compound 9): ¹HNMR (CDCl₃) δ 7.67 (dd, 1H), 7.22 (dd, 1H), 5.52 (br s, 2H), 5.23 (dd,1H), 4.9 (dd, 1H), 3.99 (d, 3H), 3.95 (s, 3H).

6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-(1-ethoxyvinyl)pyrimidine-4-carboxylicacid methyl ester (Compound 10): ¹H NMR (CDCl₃) δ 7.62 (dd, 1H), 7.2(dd, 1H), 5.62 (br s, 2H), 4.5 (dd, 2H), 3.99 (d, 3H), 3.92 (q, 2H),3.91 (s, 3H), 1.37 (t, 3H).

4-tert-Butoxycarbonylamino-6-(4-chlorophenyl)-5-fluoro-3-(1-fluorovinyl)-pyridine-2-carboxylicacid methyl ester (utilized tributyl-(1-fluorovinyl)-stannane preparedaccording to the procedures found in Bull. Chem. Soc. Jpn. 2002, 75(11),2497-2502): ¹H NMR (CDCl₃) δ 7.96 (m, 2H), 7.46 (m, 2H), 6.35 (br s,1H), 5.25 (dd, 1H), 4.85 (dd, 1H), 3.96 (s, 3H). This compound is thestarting material for Compound 30 in Example 29.

19. Preparation of6-Amino-2-(4-chloro-2,3-difluorophenyl)-5-vinyl-pyrimidine-4-carboxylicacid methyl ester (Compound 11)

6-Amino-2-chloro-5-vinylpyrimidine-4-carboxylic acid methyl ester (0.6g, 2.81 mmol),2-(4-chloro-2,3-difluorophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane(1.0 g, 3.65 mmol), bis(triphenylphosphine)-palladium(II) dichloride(197 mg, 0.28 mmol), and cesium fluoride (0.85 g, 5.6 mmol) werecombined in 10 mL of 1,2-dimethoxyethane (DME) and 10 mL of water. Thereaction mixture was heated in a CEM microwave reactor at 100° C. for 15min (other temperature/time pairs used in the subsequent examples were110° C. for 15 min; 150° C. for 5 min). The cooled reaction mixture wasdiluted with ethyl acetate, washed with water, dried and concentrated.The product was purified by flash chromatography on silica gel (ethylacetate/hexane gradient) to yield the title compound (0.336 g, 36.7%yield) as a yellow solid (mp 130-132° C.); ¹H NMR (CDCl₃) δ 7.74 (m,1H), 7.22 (m, 1H), 6.8 (dd, 1H), 5.62-5.7 (m, 2H), 5.67 (m, 1H), 5.42(br s, 2H), 3.94 (s, 3H).

Other compounds prepared by the method of Example 19 include:

6-Amino-2-(4-chloro-2,5-difluorophenyl)-5-vinylpyrimidine-4-carboxylicacid methyl ester (Compound 12): ¹H NMR (CDCl₃) δ 7.84 (dd, 1H), 7.22(dd, 1H), 6.81 (dd, 1H), 5.62-5.70 (m, 2H), 5.41 (br s, 2H), 3.92 (s,3H).

6-Amino-2-(4-chloro-2-fluoro-5-methylphenyl)-5-vinylpyrimidine-4-carboxylicacid methyl ester (Compound 13): ¹H NMR (CDCl₃) δ 7.83 (d, 1H), 7.18 (d,1H), 6.81 (dd, 1H), 5.6-5.71 (m, 2H), 5.41 (br s, 2H), 3.92 (s, 3H),2.38 (s, 3H).

6-amino-2-(4-chloro-2-fluoro-3-(1-fluoroethyl)phenyl)-5-vinylpyrimidine-4-carboxylicacid methyl ester (Compound 14): mp 144-147° C. ¹H NMR (CDCl₃) δ 7.88(m, 1H), 7.25 (m, 1H), 6.83 (dd, 1H, J=12, 18 Hz), 6.17 (dq, 1H, J=6, 46Hz), 5.62-5.72 (m, 2H), 5.46 (br s, 2H), 3.95 (s, 3H), 1.79 (ddd, 3H,J=1, 7, 23 Hz).

6-Amino-2-(4-chloro-3-difluoromethyl-2-fluorophenyl)-5-vinylpyrimidine-4-carboxylicacid methyl ester (Compound 15): ¹H NMR (CDCl₃) δ 8.07 (m, 1H), 7.31 (brd, 1H, J=8 Hz), 7.03 (dd, 1H, J=1, 53 Hz), 6.83 (dd, 1H, J=12.5, 18 Hz),5.63-5.73 (m, 2H), 5.44 (br s, 2H), 3.95 (s, 3H).

6-Amino-2-(4-chloro-3-fluorophenyl)-5-vinylpyrimidine-4-carboxylic acidmethyl ester (Compound 16): ¹H-NMR (CDCl₃) δ 8.19-8.11(m, 2H) 7.44 (t,J=7.9 Hz, s, 1H), 6.79 (dd, J=11, 6 Hz 1H), 5.68-5.60 (m, 2H), 5.36 (s,2H), 3.95 (s, 3H).

6-Amino-2-(4-chloro-3-difluoromethoxy-2-fluorophenyl)-5-vinylpyrimidine-4-carboxylicacid methyl ester (Compound 17): ¹H-NMR (CDCl₃) δ 7.87 (t, J=8.6 Hz, 1H)7.30 (dd, J=6.92, 1.65 Hz, 1H), 6.82 (dd, J=11, 6 Hz, 1H), 6.63 (t, J=73Hz, 1H), 5.8 (dd, J=7.26, 1.3 Hz, 2H), 5.46(s, 2H), 3.94(s, 3H).

6-Amino-2-(2,4-dichloro-3-methoxyphenyl)-5-vinylpyrimidine-4-carboxylicacid methyl ester (Compound 18): ¹H NMR (CDCl₃) δ 7.38 (s, 2H), 6.83(dd, 1H), 5.63-5.7 (m, 2H), 5.53 (br s, 2H), 3.92 (s, 3H), 3.91 s, 3H).

6-Amino-2-(4-chloro-3-dimethylamino-2-fluorophenyl)-5-vinylpyrimidine-4-carboxylicacid methyl ester (Compound 19): ¹H NMR (CDCl₃) δ 7.57 (dd, 1H), 7.2(dd, 1H), 6.83 (dd, 1H), 5.62-5.70 (m, 2H), 5.42 (br s, 2H), 3.94 (s,3H), 2.9 (d, 6H).

6-Amino-2-[4-chloro-3-(1-fluoroethyl)phenyl]-5-vinylpyrimidine-4-carboxylicacid methyl ester (Compound 20): ¹H NMR (CDCl₃) δ 8.53 (m, 1H), 8.26 (m,1H), 7.40 (m, 1H), 6.78 (dd, 1H), 5.99 (dt, 1H), 5.6-5.66 (m, 2H), 5.35(br s, 2H), 3.95 (s, 3H), 1.69 (dd, 3H).

20. Preparation of6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-ethyl-pyrimidine-4-carboxylicacid methyl ester (Compound 21)

6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-vinyl-pyrimidine-4-carboxylicacid methyl ester (200 mg, 0.7 mmol) was dissolved in ethanol (10 mL),palladium hydroxide (20% on carbon, 50 mg) was added, and the reactionmixture was stirred under an atmosphere of hydrogen for 4 h. Thecatalyst was then filtered off, the filtrate concentrated, and theproduct purified by flash chromatography on silica gel (hexane/ethylacetate gradient) to yield the title compound (148 mg, 62% yield): mp144-146° C.: ¹H NMR (CDCl₃) δ 7.61 (m, 1H), 7.20 (m, 1H), 5.19 (br s,2H), 3.99 (d, 3H), 3.98 (s, 3H), 2.68 (q, 2H), 1.28 (t, 3H).

21. Preparation of6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-((E)-propenyl)pyrimidine-4-carboxylicacid methyl ester (Compound 22)

6-Amino-5-bromo-2-(4-chloro-2-fluoro-3-methoxyphenyl)-pyrimidine-4-carboxylicacid methyl ester (400 mg, 1.02 mmol), trans-propenyl boronic acid (2132mg, 1.54 mmol), bis(triphenylphosphine)palladium(II) dichloride (72 mg,0.1 mmol), and cesium fluoride (311 mg, 2.05 mmol) were combined in1,2-dimethoxyethane (2 mL) and water (2 mL) and heated at 100° C. for 15min in a CEM microwave reactor. The cooled reaction mixture waspartitioned between ethyl acetate and water; and the organic phase wasdried and concentrated. The product was purified by flash chromatographyon silica gel (hexane/ethyl acetate gradient) then purified again byreverse phase HPLC to yield the title compound: mp 133-135° C.: ¹H NMR(CDCl₃) δ 7.63 (m, 1H), 7.22 (m, 1H), 6.43 (m, 1H), 6.12 (m, 1H), 5.35(br s, 2H), 3.99 (d, 3H), 3.94 (s, 3H), 1.94 (dd, 3H).

Another compound prepared by the method of Example 21 is:

6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-((Z)-propenyl)pyrimidine-4-carboxylicacid methyl ester (Compound 23): mp 91-93° C.: ¹H NMR (CDCl₃) δ 7.67 (m,1H), 7.22 (m, 1H), 6.38 (m, 1H), 6.07 (m, 1H), 5.32 (br s, 2H), 4.0 (d,3H), 3.93 (s, 3H).

22. Preparation of6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-trimethylsilanylethynylpyrimidine-4-carboxylicacid methyl ester

6-Amino-5-bromo-2-(4-chloro-2-fluoro-3-methoxyphenyl)-pyrimidine-4-carboxylicacid methyl ester (1.0 g, 2.56 mmol),trimethyl((tributylstannyl)ethynyl)silane (1.98 g, 5.12 mmol), andbis(triphenylphosphine)palladium(II) dichloride (0.18 g, 0.256 mmol)were combined in 1,2-dichloroethane (10 mL) and heated in a CEMmicrowave reactor at 110° C. for 15 min. The cooled reaction mixture wasconcentrated under vacuum then purified by flash chromatography onsilica gel (dichloromethane/ethyl acetate gradient). A secondpurification by flash chromatography on silica gel (hexane/ethyl acetategradient) yielded the title compound (0.829 g, 79% yield): mp 126-128°C.

23. Preparation of6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-ethynyl-pyrimidine-4-carboxylicacid methyl ester (Compound 24)

6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-trimethyl-silanylethynylpyrimidine-4-carboxylicacid methyl ester (1.2 g, 2.94 mmol) was dissolved in methanol (20 mL)and potassium carbonate (0.203 g, 1.471 mmol) was added. After 1 hstirring at ambient temperature, the precipitate that formed wasfiltered off, washed with methanol, dissolved in dichloromethane andwashed with water. The organic phase was dried and concentrated to yieldthe title compound (0.410 g, 41.5% yield): mp 174-176° C.: ¹H NMR(CDCl₃) δ 7.7 (m, 1H), 7.22 (m, 1H), 5.82 (br s, 2H), 4.01 (s, 3H), 4.00(dd, 3H), 3.85 (s, 1H).

24. Preparation of4-Amino-6-(4-chlorophenyl)-5-fluoro-3-methylpyridine-2-carboxylic acidmethyl ester (Compound 25)

4-Amino-3-chloro-6-(4-chlorophenyl)-5-fluoropyridine-2-carboxylic acidmethyl ester (0.400 g, 1.269 mmol), tetramethylstannane (3.41 g, 19.04mmol), and bis(triphenylphosphine)palladium(II) dichloride (0.089 g,0.127 mmol) were combined and heated to 130° C. for 25 min in a CEMmicrowave reactor. The cooled reaction mixture was concentrated ontosilica gel and purified by flash chromatography on silica gel (ethylacetate/hexane gradient) to yield the title compound (0.143 g, 38.2%yield): ¹H NMR (CDCl₃) δ 7.88 (m, 2H), 7.41 (m, 2H), 4.41 (br s, 2H),3.96 (s, 3H), 2.36 (s, 3H).

25. Preparation of4-Acetylamino-6-(4-chloro-2-fluoro-3-methoxyphenyl)-3-methylpyridine-2-carboxylicacid methyl ester

4-Acetylamino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-pyridine-2-carboxylicacid methyl ester (500 mg, 1.29 mmol), tetramethyltin (924 mg, 5.17mmol), bis(triphenylphosphine)palladium(II) dichloride (91 mg, 0.129mmol), and tetrabutylammonium triphenyldifluorosilicate (1.395 g, 2.58mmol) were combined in 2 mL of acetonitrile and heated in a CEMmicrowave reactor at 110° C. for 15 min. The resulting reaction mixturewas filtered and concentrated. This intermediate product was purified byflash chromatography on silica gel (ethyl acetate/hexane gradient) toyield the title compound (419 mg, 88% yield). mp 182-184° C.

26. Preparation of4-tert-Butoxycarbonylamino-3-chloro-6-(4-chlorophenyl)-5-fluoropyridine-2-carboxylicacid methyl ester

4-Amino-3-chloro-6-(4-chlorophenyl)-5-fluoropyridine-2-carboxylic acidmethyl ester (3 g, 9.5 mmol) was dissolved in dichloromethane (50 mL)and di-tert-butyl dicarbonate (4.6 g, 21 mmol) was added at ambienttemperature. After 1 h, the reaction mixture was concentrated and theproduct was purified by flash chromatography on silica gel (ethylacetate/hexane gradient). This bis-protected intermediate (3.2 g, 6.2mmol) was then dissolved in dichloromethane (25 mL) and trifluoroaceticacid (1.42 g, 12.4 mmol) was added. The reaction mixture was stirred for4 h at ambient temperature then concentrated under vacuum. The productwas purified by flash chromatography on silica gel to yield the titlecompound (2 g, 4.82 mmol, 50.7% yield for the two steps) as a whitesolid: ¹H NMR (CDCl₃) δ 7.91 (m, 2H), 7.43 (m, 2H), 6.48 (br s, 1H), 4.0(s, 3H), 1.55 (s, 9H).

27. Preparation of4-Amino-6-(4-chlorophenyl)-5-fluoro-3-vinylpyridine-2-carboxylic acidmethyl ester (Compound 26)

4-Amino-3-chloro-6-(4-chlorophenyl)-5-fluoropyridine-2-carboxylic acidmethyl ester (0.5 g, 1.59 mmol), tributyl(vinyl)tin (1.01 g, 3.17 mmol),bis(triphenylphosphine)palladium(II) dichloride (0.111 g, 0.159 mmol),and tetrabutylammonium triphenyldifluorosilicate (1.71 g, 3.17 mmol)were combined in acetonitrile (3 ml) and heated to 110° C. for 15 min ina CEM microwave reactor. The cooled reaction mixture was concentratedonto silica gel and purified by flash chromatography on silica gel(hexane/ethyl acetate gradient) twice to yield the title compound (46mg, 5% yield) as an off-white solid, mp 81-83° C. ¹H NMR (CDCl₃) δ 7.9(m, 1H), 7.43 (m, 1H), 6.89 (dd, 1H), 5.7 (dd, 1H), 5.57 (dd, 1H), 4.72(br s, 2H), 3.93 (s, 3H).

28. Preparation of4-Acetylamino-6-(4-chloro-2-fluoro-3-methoxyphenyl)-3-vinylpyridine-2-carboxylicacid methyl ester

4-Acetylamino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylicacid methyl ester (0.5 g, 1.29 mmol), tributyl(vinyl)tin (0.821 g, 2.58mmol), bis(triphenylphosphine)palladium(II) dichloride (0.091 g, 0.129mmol), and tetrabutylammonium triphenyldifluorosilicate (1.4 g, 2.58mmol) were combined in acetonitrile (3 ml) and heated to 110° C. for 15min in a CEM microwave reactor. The cooled reaction mixture wasconcentrated onto silica gel and purified by flash chromatography onsilica gel (ethyl acetate/hexane gradient) to yield the title compound(0.293 g, 60% yield) as a white solid, mp 143-145° C. ¹H NMR (CDCl₃) δ7.66 (m, 1H), 7.22 (d, 1H), 7.12 (m, 1H), 6.85 (dd, 1H), 5.66 (dd, 1H),5.57 (dd, 1H), 4.61 (br s, 2H), 3.97 (s, 3H), 3.94 (d, 3H).

Other compounds prepared by the method of Example 28 include:

4-Acetylamino-6-(4-chloro-2-fluorophenyl)-3-vinylpyridine-2-carboxylicacid methyl ester.

29. Preparation of4-Amino-6-(4-chloro-2-fluoro-3-methoxyphenyl)-3-methyl-pyridine-2-carboxylicacid methyl ester (Compound 27)

4-Acetylamino-6-(4-chloro-2-fluoro-3-methoxyphenyl)-3-methylpyridine-2-carboxylicacid methyl ester (369 mg, 1.0 mmol) was dissolved in methanol (10 mL)and acetyl chloride (1.07 mL, 15 mmol) was added. The reaction mixturewas stirred overnight at ambient temperature and concentrated undervacuum. The residue was partitioned between ethyl acetate and aqueoussodium bicarbonate; and the organic phase was dried and concentrated.Purification by flash chromatography on silica gel(dichloromethane/ethyl acetate gradient) followed by a secondpurification by flash chromatography (hexane/ethyl acetate gradient)yielded the title compound (292 mg, 88% yield) as a white solid, mp122-125° C. ¹H NMR (CDCl₃) δ 7.65 (m, 1H), 7.26 (s, 1H), 7.1 (m, 1H),4.35 (br s, 2H), 3.99 (s, 3H), 3.98 (d, 3H), 2.31 (s, 3H).

Other compounds prepared by the method of Example 29 include:

4-Amino-6-(4-chloro-2-fluoro-3-methoxyphenyl)-3-vinylpyridine-2-carboxylicacid methyl ester (Compound 28): mp 118-121° C.: ¹H NMR (CDCl₃) δ 7.67(m, 1H), 7.24 (d, 1H), 7.13 (m, 1H), 6.86 (dd, 1H), 5.55-5.71 (m, 2H),4.63 (br s, 2H), 3.99 (s, 3H), 3.94 (s, 3H).

4-Amino-6-(4-chloro-2-fluorophenyl)-3-vinylpyridine-2-carboxylic acidmethyl ester (Compound 29). ¹H NMR (CDCl₃) δ 8.0 (m, 1H), 7.2 (d, 1H),7.1 (m, 2H), 6.8 (m, 1H), 5.6 (m, 2 h), 4.6 (s, 2H), 3.9 (s, 3H).

4-Amino-6-(4-chlorophenyl)-5-fluoro-3-(1-fluorovinyl)pyridine-2-carboxylicacid methyl ester (Compound 30): ¹H NMR (CDCl₃) δ 7.9 (m, 2H), 7.43 (m,2H), 5.27 (dd, 1H), 4.84 (dd, 1H), 4.87 (br s, 2H).

30. Preparation of4-Acetylamino-6-(4-chloro-2-fluoro-3-methoxyphenyl)-3-trimethylsilanylethynylpyridine-2-carboxylicacid methyl ester

4-Acetylamino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-pyridine-2-carboxylicacid methyl ester (0.8 g, 2.061 mmol),trimethyl((tributylstannyl)ethynyl)silane (1.596 g, 4.12 mmol), andbis(triphenylphosphine)palladium(II) dichloride (0.145 g, 0.206 mmol)were combined in 1,2-dichloroethane (2 mL) and heated in a CEM microwavereactor at 130° C. for 15 min. The cooled reaction mixture was purifiedby flash chromatography on silica gel (hexane/ethyl acetate gradient) toyield the title compound (0.196 g, 21.1% yield). ¹H NMR (CDCl₃) δ 9.03(s, 1H), 8.4 (br s, 1H), 7.67 (m, 1H), 7.24 (m, 1H), 4.0 (s, 3H), 3.99(d, 3H), 2.29 (s, 3H), 0.36 (s, 9H).

31. Preparation of4-Amino-6-(4-chloro-2-fluoro-3-methoxyphenyl)-3-ethynyl-pyridine-2-carboxylicacid methyl ester (Compound 31)

4-Acetylamino-6-(4-chloro-2-fluoro-3-methoxyphenyl)-3-trimethylsilanylethynylpyridine-2-carboxylicacid methyl ester (0.196 g, 0.437 mmol) was suspended in methanol (4.36mL) and acetyl chloride (0.310 mL, 4.37 mmol) was added. The reactionmixture was stirred overnight at ambient temperature then concentratedto dryness. The residue was dissolved in methanol (4.36 mL) andpotassium carbonate (0.121 g, 0.873 mmol) was added. The reactionmixture was stirred at ambient temperature for 2 h, acidified with 2NHCl, and concentrated but not to dryness. The residue was partitionedbetween ethyl acetate and sodium bicarbonate; and the organic phase wasdried and concentrated. The resulting product was purified by flashchromatography on silica gel (ethyl acetate/hexane gradient) to yieldthe title compound (0.109 g, 74.6% yield) as a yellow solid, mp 167-169°C.: ¹H NMR (CDCl₃) δ 7.7 (m, 1H), 7.24 (s, 1H), 7.18 (m, 1H), 5.08 (brs, 2H), 3.99 (s, 3H), 3.97 (d, 3H), 3.84 (s, 1H).

32. Preparation of5-Acetyl-6-amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-pyrimidine-4-carboxylicacid methyl ester (Compound 32)

6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-(1-ethoxy-vinyl)pyrimidine-4-carboxylicacid methyl ester (0.235 g, 0.616 mmol) was dissolved in THF (5 mL) and2N HCl (0.616 mL, 1.231 mmol) and stirred at ambient temperature for 3h. The reaction mixture was concentrated, triturated with water, andfiltered. The product was washed with methanol and dried under vacuum toyield the title compound (0.205 g, 94% yield): ¹H NMR (DMSO-d₆) δ 7.7(br s, 2H), 7.63 (dd, 1H), 7.42 (dd, 1H), 3.92 (s, 3H), 3.85 (s, 3H),2.46 (s, 3H).

33. Preparation of6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-formyl-pyrimidine-4-carboxylicacid methyl ester (Compound 33)

6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-vinyl-pyrimidine-4-carboxylicacid methyl ester (0.500 g, 1.5 mmol) was dissolved in THF (3 mL) andwater (3 mL). Osmium tetroxide (4 mg, 0.015 mmol) was added and thereaction mixture was stirred for 2 min. Sodium periodate (0.63 g, 3mmol) was then added over a period of 2 min. The reaction mixture wasstirred for 16 h at ambient temperature then poured into water (150 mL)and extracted with dichloromethane thrice. The combined organic layerswere dried, filtered and concentrated to afford the title compound (490mg, 98% yield) in sufficient purity for subsequent reactions. Ananalytical sample was obtained by reverse phase chromatography: ¹H NMR(CDCl₃) δ 10.31 (s, 1H), 8.72 (br s, 1H), 7.77 (dd, 1H), 7.23 (m, 1H),6.03 (br s, 1H), 4.06 (s, 3H), 4.01 (d, 3H).

Another compound prepared by the method of Example 33 is:

4-Amino-6-(4-chloro-2-fluoro-3-methoxyphenyl)-3-formylpyridine-2-carboxylicacid methyl ester (Compound 34): ¹H-NMR (CDCl₃) δ 10.27 (s,1H), 7.75 (t,J=8.6 Hz, 1H) 7.28 (dd, J=8.6 1.9 Hz, 1H) 7.25 (d, J=1.7 Hz, 1H), 7.12(m, 2H), 5.3 (s, 2H), 4.03( s, 3H) 3.98 (d, J=1.0 Hz, 3H).

34. Preparation of6-Amino-2-(4-chloro-2-fluoro-3-methoxy-phenyl)-5-difluoromethylpyrimidine-4-carboxylicacid methyl ester (Compound 35)

6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-formylpyrimidine-4-carboxylicacid methyl ester (0.120, 0.35 mmol) was dissolved in dichloromethane (5mL) and diethyl ether (3 mL) with gentle heating. After allowing thesolution to cool to ambient temperature, diethylaminosulfur trifluoride(0.5 g, 3.15 mmol) was added and the reaction mixture was gently heatedto obtain a clear solution. The reaction mixture was stirred overnightat ambient temperature then quenched with methanol and concentratedunder vacuum. The product was purified by flash chromatography on silicagel (ethyl acetate/hexane gradient) to yield the title compound (62 mg,48% yield): ¹H NMR (CDCl₃) δ 7.69 (dd, 1H), 7.42 (t, 1H), 7.24 (dd, 1H),5.83 (br s, 2H), 4.02 (s, 3H), 4.0 (d, 3H).

Another compound prepared by the method of Example 34 is:

4-Amino-6-(4-chloro-2-fluoro-3-methoxyphenyl)-3-difluoromethylpyridine-2-carboxylicacid methyl ester (Compound 36): ¹H-NMR (CDCl₃) δ 7.76 (t, J=8.2 Hz, 1H)7.40 (t, J=53.4 Hz, s, 1H) 7.23 (m, 1H), 7.14 (m, 1H), 5.09 (s, 2H),3.99 (s, 3H), 3.97 (s, 3H).

35. Preparation of6-Amino-5-((E)-2-bromovinyl)-2-(4-chloro-2-fluoro-3-methoxyphenyl)pyrimidine-4-carboxylicacid methyl ester (Compound 37)

6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-vinylpyrimidine-4-carboxylicacid methyl ester (0.720 g, 2.13 mmol) was dissolved in chloroform (20mL) and bromine (0.511 g, 3.2 mmol) was added. The reaction mixture wasstirred at ambient temperature for 2 h then concentrated under vacuum.The product was dissolved in dichloromethane (20 mL), treated withtriethylamine (0.430 g, 4.26 mmol), stirred at ambient temperature for 2h, and then concentrated under vacuum. The product was purified by flashchromatography on silica gel (dichloromethane/ethyl acetate gradient) toprovide the title compound (0.5 g, 56% yield over two steps) as a whitesolid, mp 171-173° C.: ¹H NMR (CDCl₃) δ 7.66 (dd, 1H), 7.22 (dd, 1H),7.22 (d, 1H), 6.72 (d, 1H), 5.37 (br s, 2H), 4.0 (s, 3H), 3.97 (s, 3H).

36. Preparation of6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-((E)-2-methylsulfanylvinyl)pyrimidine-4-carboxylicacid methyl ester (Compound 38)

6-Amino-5-((E)-2-bromovinyl)-2-(4-chloro-2-fluoro-3-methoxy-phenyl)pyrimidine-4-carboxylicacid methyl ester (0.915 g, 2.196 mmol) was dissolved in DMSO (10 mL)and sodium thiomethoxide (0.169 g, 2.416 mmol) was added. After 30 minat ambient temperature, the reaction mixture was diluted with water andextracted with ethyl acetate. The organic phase was diluted withpetroleum ether to decrease the solubility of residual DMSO, washed withwater thrice, filtered and concentrated. The product was purified byflash chromatography (hexane/ethyl acetate gradient) to provide thetitle compound (0.510 g, 60.5% yield) as a yellow solid: ¹H NMR (CDCl₃)δ 7.63 (dd, 1H), 7.19 (dd, 1H), 6.74 (d, 1H), 6.32 (d, 1H), 5.34 (br s,2H), 3.99 (d, 3H), 3.94 (s, 3H), 2.41 (s, 3H).

37. Preparation of6-Amino-5-(2-bromo-1-fluoroethyl)-2-(4-chloro-2-fluoro-3-methoxyphenyl)pyrimidine-4-carboxylicacid methyl ester

6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-vinyl-pyrimidine-4-carboxylicacid methyl ester (0.611 g, 1.809 mmol) and N-bromosuccinimide (0.386 g,2.171 mmol) were dissolved in dichloromethane (10 ml) and the reactionmixture was cooled to 0° C. Triethylamine trihydrofluoride (0.884 mL,5.43 mmol) was then added dropwise and the reaction mixture was allowedto warm to ambient temperature and stirred overnight. Water andadditional dichloromethane were added. Sodium bicarbonate (0.760 g, 9.05mmol) was added in several portions until no further gas evolution wasnoted. The organic phase was dried and concentrated under vacuum. Theproduct was purified by flash chromatography on silica gel twice (firstwith dichloromethane/ethyl acetate gradient followed by hexane/ethylacetate gradient) to provide the title compound (352 mg, 0.806 mmol,44.6% yield) as a white solid, mp 144-146° C.: ¹H NMR (CDCl₃) δ 7.67(dd, 1H), 7.23 (dd, 1H), 6.32 (ddd, 1H), 5.77 (br s, 2H), 4.01 (s, 3H),4.0 (d, 3H), 3.77-3.94 (m, 2H).

38. Preparation of6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-(1-fluoroethyl)pyrimidine-4-carboxylicacid methyl ester (Compound 39)

6-Amino-5-(2-bromo-1-fluoroethyl)-2-(4-chloro-2-fluoro-3-methoxyphenyl)pyrimidine-4-carboxylicacid methyl ester (324 mg, 0.742 mmol), tri-n-butyltin hydride (0.396mL, 1.484 mmol), and 2,2′-azobisisobutyronitrile (3.05 mg, 0.019 mmol)were combined in 1,2-dimethoxyethane (2.5 mL) and heated at 100° C. for15 min in a CEM microwave reactor. The cooled reaction mixture wasconcentrated under vacuum then purified by flash chromatography onsilica gel (dichloromethane/ethyl acetate gradient). A secondpurification by flash chromatography on silica gel (hexane/ethyl acetategradient) yielded the title compound (162 mg, 61.0% yield) as a whitesolid, mp 150-152° C.: ¹H NMR (CDCl₃) δ 7.64 (dd, 1H), 7.22 (dd, 1H),6.26 (dq, 1H), 5.73 (br s, 2H), 4.00 (d, 3H), 3.98 (s, 3H), 1.80 (dd,3H).

39. Preparation of6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-(1-methoxyethyl)pyrimidine-4-carboxylicacid (Compound 40)

6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-(1-fluoroethyl)pyrimidine-4-carboxylicacid methyl ester (0.100 g, 0.280 mmol) was dissolved/suspended inmethanol (10 mL) and 2N sodium hydroxide (0.561 mL, 1.121 mmol) wasadded. The reaction mixture was stirred overnight at ambienttemperature, acidified with 2N HCl, and concentrated. The precipitatethat formed was filtered, washed with water, and dried to provide thetitle compound (0.085 g, 85% yield) as a white solid, mp 165-167° C.: ¹HNMR (DMSO-d₆ and drop of D₂O) δ 7.60 (dd, 1H), 7.39 (dd, 1H), 4.55 (q,1H), 3.91 (s, 3H), 3.17 (s, 3H), 1.41 (dd, 3H).

40. Preparation of6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-vinylpyrimidine-4-carboxylicacid (Compound 41)

6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-vinylpyrimidine-4-carboxylicacid methyl ester (200 mg, 0.59 mmol) was dissolved in methanol (15 mL)and 2N sodium hydroxide (1 mL, 2 mmol) was added. The reaction mixturewas stirred at ambient temperature for 2 h, acidified with a slightexcess of 2N HCl, and concentrated. The crystals that formed werefiltered off, washed with water, washed with diethyl ether, and driedunder vacuum to yield the title compound (136 mg, 71% yield): mp167-168° C.: ¹H NMR (DMSO-d₆ and drop of D₂O) δ 7.62 (m, 1H), 7.43 (m,1H), 6.65 (dd, 1H), 5.67 (m, 2H), 3.92 (d, 3H).

Other compounds prepared by the method of Example 40 include:

6-Amino-2-(4-chloro-2-fluorophenyl)-5-vinylpyrimidine-4-carboxylic acid(Compound 42): mp 167-169° C.: ¹H NMR (DMSO-d₆ and drop of D₂O) δ 7.91(m, 1H), 7.51 (m, 1H), 7.40 (m, 1H), 6.65 (dd, 1H), 5.58 (m, 2H).

6-Amino-2-(4-chlorophenyl)-5-vinylpyrimidine-4-carboxylic acid (Compound43): ¹H NMR (DMSO-d₆) δ 13.6 (bs, 1H), 8.26 (d, 2H), 7.53 (d, 2H), 7.19(bs, 2H), 6.66 (m, 1H), 5.54 (m, 2H). 5.63 (dd, 1H), 5.56 (dd, 1H).

6-amino-2-(4-chloro-2,3-difluorophenyl)-5-vinylpyrimidine-4-carboxylicacid (Compound 44): mp 170-172° C.: ¹H NMR (DMSO-d₆ and drop of D₂O) δ7.76 (m, 1H), 7.51 (m, 1H), 6.63 (dd, 1H), 5.52-5.61 (m, 2H).

6-Amino-2-(4-chloro-3-methoxyphenyl)-5-vinylpyrimidine-4-carboxylic acid(Compound 45): ¹H NMR (DMSO-d₆) δ 7.96 (m, 1H), 7.88 (m, 1H), 7.52 (m,1H), 7.20 (br s, 2H), 6.65 (dd, 1H), 5.48-5.61 (m, 2H), 3.93 (s, 3H).

6-Amino-2-(4-chloro-2,5-difluorophenyl)-5-vinylpyrimidine-4-carboxylicacid (Compound 46): ¹H NMR (CDCl₃ plus DMSO-d₆) δ 7.79 (dd, 1H), 7.07(dd, 1H), 6.82 (dd, 1H), 6.02 (br s, 2H), 5.55-5.57 (m, 2H).

6-Amino-2-(4-chloro-2-fluoro-3-(1-fluoroethyl)phenyl)-5-vinylpyrimidine-4-carboxylicacid (Compound 47): mp 150-153° C. ¹H NMR (300 MHz, DMSO-d₆) δ 7.86 (brt, 1H, J=8 Hz), 7.46 (br d, 1H, J=8 Hz), 7.27 (br s, 2H), 6.65 (dd, 1H,J=12, 18 Hz), 6.16 (dq, 1H, J=6, 46 Hz), 5.49-5.65 (m, 2H), 1.73 (dd,3H, J=7, 23 Hz).

6-Amino-2-(4-chloro-3-difluoromethyl-2-fluorophenyl)-5-vinylpyrimidine-4-carboxylicacid (Compound 48): ¹H NMR (DMSO-d₆) δ 8.06 (t, 1H, J=8 Hz), 7.57 (d,1H, J=8 Hz), 7.13-7.43 (m, 4H), 6.66 (dd, 1H, J=11, 17 Hz), 5.51-5.67(m, 2H).

6-Amino-2-(4-chloro-3-fluorophenyl)-5-vinylpyrimidine-4-carboxylic acid(Compound 49): ¹H-NMR (DMSO-d₆) δ 8.17 (m, 2H,) 7.55 (m, 1H), 6.76 (dd,J=11, 6 Hz, 1H), 5.64-5.58 (m, 2H).

6-Amino-2-(4-chloro-3-difluoromethoxy-2-fluorophenyl)-5-vinylpyrimidine-4-carboxylicacid (Compound 50): ¹H-NMR (DMSO-d₆) δ 13.61 (s, 1H) 7.85 (t, J=8 Hz,1H), 7.53 (dd, J=7, 1.7 Hz, 1H), 7.29 (bs, 2H), 7.23 (t, J=72 Hz,1H),6.62 (dd, J=11, 6 Hz, 1H), 5.61-5.49(m, 2H).

6-Amino-2-(4-chloro-3-dimethylamino-2-fluorophenyl)-5-vinylpyrimidine-4-carboxylicacid (Compound 51): ¹H NMR (DMSO-d₆ plus drop of D₂O) δ 7.55 (dd, 1H),7.34 (dd, 1H), 6.63 (dd, 1H), 5.51-5.62 (m, 2H), 2.81 (d, 6H).

6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-(1-fluorovinyl)pyrimidine-4-carboxylicacid (Compound 52): ¹H NMR (DMSO-d₆ and drop of D₂O) δ 7.62 (dd, 1H),7.42 (dd, 1H), 5.23 (dd, 1H), 4.94 (dd, 1H), 3.92 (s, 3H).

6-amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-methylpyrimidine-4-carboxylicacid (Compound 53): mp 201-203° C.: ¹H NMR (DMSO-d₆ and drop of D₂O) δ7.57 (m, 1H), 7.38 (m, 1H), 2.11 (s, 3H).

6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-ethylpyrimidine-4-carboxylicacid (Compound 54): ¹H NMR (DMSO-d₆) δ 7.59 (dd, 1H), 7.37 (dd, 1H),7.18 (br s, 2H), 3.9 (s, 3H), 2.56 (q, 2H), 1.08 (t, 3H).

6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-((Z)-propenyl)pyrimidine-4-carboxylicacid (Compound 55): ¹H NMR (DMSO-d₆ and drop of D₂O) δ 7.63 (m, 1H),7.40 (m, 1H), 6.17 (dd, 1H), 5.94 (m, 1H), 1.52 (dd, 3H).

6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-ethynylpyrimidine-4-carboxylicacid (Compound 56): ¹H NMR (DMSO-d₆ and drop of D₂O) δ 7.67 (m, 1H),7.43 (m, 1H), 4.79 (s, 1H), 3.92 (s, 3H).

6-amino-2-cyclopropyl-5-vinylpyrimidine-4-carboxylic acid (Compound 57):mp 187-189° C.: ¹H NMR (DMSO-d₆) δ 7.7 (br s, 2H), 7.1 (dd, 1H),5.92-6.07 (m, 2H), 2.49 (m, 1H), 1.47 (m, 4H).

4-Amino-6-(4-chloro-2-fluoro-3-methoxyphenyl)-3-methylpyridine-2-carboxylicacid (Compound 58): ¹H NMR (DMSO-d₆ and drop of D₂O) δ 7.52 (m, 1H),7.43 (m, 1H). 3.93 (s, 3H), 2.2 (s, 3H).

4-Amino-6-(4-chloro-2-fluoro-3-methoxyphenyl)-3-vinylpyridine-2-carboxylicacid (Compound 59): ¹H NMR (DMSO-d₆) δ 7.62 (m, 1H), 7.40 (dd, 1H), 7.10(d, 1H), 6.70 (dd, 1H), 6.41 (br s, 2H), 5.45-5.57 (m, 2H), 3.92 (d,3H).

4-Amino-6-(4-chloro-2-fluorophenyl)-3-vinylpyridine-2-carboxylic acid(Compound 60), mp 209-211° C. ¹H NMR (MeOH-d₄) δ 7.65 (m, 1H), 7.46 (m,2H), 6.96 (d, 1H), 6.76 (dd, 1H), 5.75 (dd, 1H), 4.68 (dd, 1H).

4-Amino-6-(4-chlorophenyl)-5-fluoro-3-vinylpyridine-2-carboxylic acid(Compound 61): ¹H NMR (DMSO-d₆) δ 7.87 (m, 2H), 7.55 (m, 2H), 6.74 (dd,1H), 5.52-5.56 (m, 2H).

41. Preparation of6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-vinyl-pyrimidine-4-carboxylicacid butyl ester (Compound 62)

6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-vinyl-pyrimidine-4-carboxylicacid (0.150 g, 0.46 mmol), iodobutane (0.111 g, 0.60 mmol), and lithiumcarbonate (0.044 g, 0.6 mmol) were combined in DMF (1.5 mL) and heatedat 60° C. overnight. The cooled reaction mixture was concentrated andpartitioned between ethyl acetate and water. The organic phase was driedand concentrated. The product was purified by flash chromatography onsilica gel (ethyl acetate/hexane gradient) to yield the title compound(0.092 g, 52.3% yield): ¹H NMR (CDCl₃) δ 7.65 (dd, 1H), 7.19 (dd, 1H),7.75 (dd, 1H), 5.62-5.67 (m, 2H), 5.35 (br s, 2H), 4.34 (t, 3H), 3.99(dd, 3H), 1.74 (m, 2H), 1.45 (m, 2H), 0.97 (t, 3H).

42. Preparation of the triethylamine salt of6-amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-vinylpyrimidine-4-carboxylicacid (Compound 63)

6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-vinyl-pyrimidine-4-carboxylicacid (36 mg) was dissolved in 10 mL of dichloromethane by the additionof 1 mL of triethylamine. The solvent and excess triethylamine wereremoved under vacuum to yield the title compound in quantitative yield.

43. Preparation of Herbicidal Compositions

In the following illustrative compositions, parts and percentages are byweight.

Emulsifiable Concentrates Formulation A

WT % Compound 1 26.2 Polyglycol 26-3 5.2 Nonionicemulsifier-(di-sec-butyl)- phenyl-poly(oxypropylene)block polymer with(oxyethylene). The polyoxyethylene content is about 12 moles. WitconateP12-20 (Anionic emulsifier- 5.2 calcium dodecylbenzene sulfonate- 60 wt.% active) Aromatic 100 (Xylene range aromatic 63.4 solvent)

Formulation B

WT % Compound 3 3.5 Sunspray 11N (paraffin oil) 40.0 Polyglycol 26-319.0 Oleic acid 1.0 Xylene range aromatic solvent 36.5

Formulation C

WT % Compound 9 13.2 Stepon C-65 25.7 Ethomeen T/25 7.7 Ethomeen T/1518.0 Xylene range aromatic solvent 35.4

Formulation D

WT % Compound 2 30.0 Agrimer Al-10LC (emulsifier) 3.0N-methyl-2-pyrrolidone 67.0

Formulation E

WT % Compound 18 10.0 Agrimul 70-A (dispersant) 2.0 Amsul DMAP 60(thickener) 2.0 Emulsogen M (emulsifier) 8.0 Attagel 50 (suspension aid)2.0 Crop oil 76.0

These concentrates can be diluted with water to give emulsions ofsuitable concentrations for controlling weeds.

Wettable Powders Formulation F

WT % Compound 44 26.0 Polyglycol 26-3 2.0 Polyfon H 4.0 Zeosyl 100(Precipitated hydrated SiO₂) 17.0 Barden clay + inerts 51.0

Formulation G

WT % Compound 58 62.4 Polyfon H (sodium salt of lignin 6.0 sulfonate)Sellogen HR (sodium naphthalene 4.0 sulfonate) Zeosyl 100 27.6

Formulation H

WT % Compound 59 1.4 Kunigel V1 (carrier) 30.0 Stepanol ME Dry (wetter)2.0 Tosnanon GR 31A (binder) 2.0 Kaolin NK-300 Clay (filler) 64.6

The active ingredient is applied to the corresponding carriers and thenthese are mixed and ground to yield wettable powders of excellentwettability and suspension power. By diluting these wettable powderswith water it is possible to obtain suspensions of suitableconcentrations for controlling weeds.

Water Dispersible Granules Formulation I

WT % Compound 57 26.0 Sellogen HR 4.0 Polyfon H 5.0 Zeosyl 100 17.0Kaolinite clay 48.0

The active ingredient is added to the hydrated silica, which is thenmixed with the other ingredients and ground to a powder. The powder isagglomerated with water and sieved to provide granules in the range of−10 to +60 mesh. By dispersing these granules in water it is possible toobtain suspensions of suitable concentrations for controlling weeds.

Granules Formulation J

WT % Compound 50 5.0 Celetom MP-88 95.0

The active ingredient is applied in a polar solvent such asN-methylpyrollidinone, cyclohexanone, gamma-butyrolactone, etc. to theCeletom MP 88 carrier or to other suitable carriers. The resultinggranules can be applied by hand, granule applicator, airplane, etc. inorder to control weeds.

Formulation K

WT % Compound 41 1.0 Polyfon H 8.0 Nekal BA 77 2.0 Zinc Stearate 2.0Barden Clay 87.0

All materials are blended and ground to a powder then water is added andthe clay mixture is stirred until a paste is formed. The mixture isextruded through a die to provide granules of proper size.

Water Soluble Liquids Formulation L

WT % Compound 62 3.67 Monoethanolamine pH buffer 0.5 Water 95.83

The active ingredient is dissolved in an appropriate amount of water andthe additional monoethanolamine is added as a buffer. A water-solublesurfactant may be added. Other aids may be incorporated to improvephysical, chemical and/or formulation properties.

44. Evaluation of General Postemergence Herbicidal Activity

Seeds or nutlets of the desired test plant species were planted in SunGro MetroMix® 306 planting mixture, which typically has a pH of 6.0 to6.8 and an organic matter content of about 30 percent, in plastic potswith a surface area of 103 square centimeters. When required to ensuregood germination and healthy plants, a fungicide treatment and/or otherchemical or physical treatment was applied. The plants were grown for7-21 days in a greenhouse with an approximate 15 hour photoperiod whichwas maintained at about 23-29° C. during the day and 22-28° C. duringthe night. Nutrients and water were added on a regular basis andsupplemental lighting was provided with overhead metal halide 1000-Wattlamps as necessary. The plants were employed for testing when theyreached the first or second true leaf stage.

A weighed amount, determined by the highest rate to be tested, of eachtest compound was placed in a 25 mL glass vial and was dissolved in 4 mLof a 97:3 v/v (volume/volume) mixture of acetone and dimethyl sulfoxide(DMSO) to obtain concentrated stock solutions. If the test compound didnot dissolve readily, the mixture was warmed and/or sonicated. Theconcentrated stock solutions obtained were diluted with 20 mL of anaqueous mixture containing acetone, water, isopropyl alcohol, DMSO,Atplus 411F crop oil concentrate, and Triton® X-155 surfactant in a48.5:39:10:1.5:1.0:0.02 v/v ratio to obtain spray solutions containingthe highest application rates. Additional application rates wereobtained by serial dilution of 12 mL of the high rate solution into asolution containing 2 mL of 97:3 v/v (volume/volume) mixture of acetoneand dimethyl sulfoxide (DMSO) and 10 mL of an aqueous mixture containingacetone, water, isopropyl alcohol, DMSO, Atplus 411F crop oilconcentrate, and Triton X-155 surfactant in a 48.5:39:10:1.5:1.0:0.02v/v ratio to obtain 1/2X, 1/4X, 1/8X and 1/16X rates of the high rate.Compound requirements are based upon a 12 mL application volume at arate of 187 L/ha. Formulated compounds were applied to the plantmaterial with an overhead Mandel track sprayer equipped with a 8002Enozzles calibrated to deliver 187 L/ha over an application area of 0.503square meters at a spray height of 18 inches (43 cm) above the averageplant canopy height. Control plants were sprayed in the same manner withthe solvent blank.

The treated plants and control plants were placed in a greenhouse asdescribed above and watered by sub-irrigation to prevent wash-off of thetest compounds. After 14 days, the condition of the test plants ascompared with that of the untreated plants was determined visually andscored on a scale of 0 to 100 percent where 0 corresponds to no injuryand 100 corresponds to complete kill.

Some of the compounds tested, application rates employed, plant speciestested, and results are given in Table 1.

TABLE 1 Post-emergent Weed Control Rate Compound g ai/ha CHEAL ABUTHEPHHL ECHCG ORYSA 1 280 80 15 100 0 0 2 280 100 95 100 95 0 3 70 100 100100 95 15 4 140 100 100 100 0 0 5 140 100 100 100 80 5 6 280 90 100 7080 0 7 280 95 60 70 0 0 8 280 100 100 50 100 0 9 140 95 90 100 90 0 10280 40 50 75 0 0 11 70 100 100 100 90 0 12 140 100 100 50 50 0 13 280100 90 60 0 0 14 70 100 100 100 100 10 15 140 100 100 100 100 5 16 14095 100 80 0 0 17 280 100 100 100 100 0 18 140 100 100 40 90 0 19 280 100100 100 85 85 20 280 100 85 100 70 0 21 140 100 85 100 70 0 22 70 95 85100 95 0 23 70 95 85 100 95 10 24 140 85 80 85 70 0 25 280 100 70 100 00 26 140 100 100 90 70 0 27 280 30 80 100 0 0 28 280 75 85 90 75 0 29280 85 85 75 0 10 30 140 100 100 90 0 0 31 140 95 95 100 80 0 32 280 7070 100 0 0 33 229 50 80 100 0 0 34 280 90 100 95 95 0 35 280 85 75 90 00 36 280 95 100 95 95 0 37 280 90 80 90 0 10 38 280 100 90 100 60 0 39140 60 80 85 30 0 40 280 100 85 100 90 35 41 70 100 100 100 100 65 43280 100 90 100 90 35 44 70 100 100 100 100 15 45 280 95 0 60 60 0 46 140100 90 95 90 40 47 70 100 90 100 100 50 49 140 100 65 100 NT 0 50 280100 95 100 100 45 51 140 100 100 90 95 60 52 140 95 95 100 90 65 53 140100 90 100 90 0 54 280 100 90 100 90 0 55 70 100 100 100 100 15 56 14095 80 90 75 0 57 140 100 90 100 30 5 58 280 50 90 90 50 0 59 140 100 100100 100 0 60 140 100 70 80 35 15 61 140 100 100 95 NT 50 62 140 100 100100 NT 25 63 70 100 95 100 90 75 CHEAL = lambsquarter (Chenopodiumalbum) ABUTH = velvetleaf (Abutilon theophrasti) EPHHL = wild poinsettia(Euphorbia heterophylla) ECHCG = barnyardgrass (Echinochloa crus-galli)ORYSA = rice (Oryza sativa) NT = not testsed

45. Evaluation of General Preemergence Herbicidal Activity

Seeds of the desired test plant species were planted in a soil matrixprepared by mixing a loam soil (43 percent silt, 19 percent clay, and 38percent sand, with a pH of about 8.1 and an organic matter content ofabout 1.5 percent) and sand in a 70 to 30 ratio. The soil matrix wascontained in plastic pots with a surface area of 127 square centimeters.When required to ensure good germination and healthy plants, a fungicidetreatment and/or other chemical or physical treatment was applied.

A weighed amount, determined by the highest rate to be tested, of eachtest compound was placed in a 25 mL glass vial and was dissolved in 6 mLof a 97:3 v/v (volume/volume) mixture of acetone and DMSO to obtainconcentrated stock solutions. If the test compound did not dissolvereadily, the mixture was warmed and/or sonicated. The stock solutionsobtained were diluted with 18 mL of a 0.1% v/v aqueous solution ofTween® 20 surfactant to obtain spray solutions containing the highestapplication rate. Additional application rates were obtained by serialdilution of 12 mL of the high rate solution into a solution containing 3mL of 97:3 v/v mixture of acetone and DMSO and 9 mL of the 0.1% v/vaqueous solution of Tween® 20 surfactant to obtain 1/2X, 1/4X, 1/8X and1/16X rates of the high rate. Compound requirements are based upon a 12mL application volume at a rate of 187 L/ha. Formulated compounds wereapplied to the soil surface with an overhead Mandel track sprayerequipped with a 8002E nozzles calibrated to deliver 187 L/ha over anapplication area of 0.503 square meters at a spray height of 18 inches(43 cm) above the soil surface. Control pots were sprayed in the samemanner with the solvent blank.

The treated pots and control pots were placed in a greenhouse maintainedwith an approximate 15 hour photoperiod and temperatures of about 23-29°C. during the day and 22-28° C. during the night. Nutrients and waterwere added on a regular basis and supplemental lighting was providedwith overhead metal halide 1000-Watt lamps as necessary. The water wasadded by top-irrigation. After 20-22 days, the condition of the testplants that germinated and grew as compared with that of the untreatedplants that emerged and grew was determined visually and scored on ascale of 0 to 100 percent where 0 corresponds to no injury and 100corresponds to complete kill or no emergence.

Some of the compounds tested, application rates employed, plant speciestested, and results are given in Table 2.

TABLE 2 Pre-emergent Weed Control Rate Compound g ai/ha CHEAL ABUTHEPHHL ECHCG ORYSA 1 140 100 80 100 80 30 2 140 80 40 95 0 15 3 140 10080 100 80 30 4 280 100 90 100 50 0 5 140 95 100 90 0 10 11 70 100 100100 100 95 14 140 100 100 100 95 95 21 140 40 60 80 0 0 28 140 95 95 10070 20 42 140 100 100 100 30 10 43 140 100 100 100 90 90 45 140 60 0 0 1030 53 140 100 100 100 80 0 55 140 100 100 100 60 30 59 140 100 100 100100 0 CHEAL = lambsquarter (Chenopodium album) ABUTH = velvetleaf(Abutilon theophrasti) EPHHL = wild poinsettia (Euphorbia heterophylla)ECHCG = barnyardgrass (Echinochloa crus-galli) ORYSA = rice (Oryzasativa)

What is claimed is:
 1. A compound selected from the group consisting of

or an agriculturally acceptable salt or ester thereof.
 2. The compoundof claim 1, wherein the compound is:

or corresponding carboxylic acid.
 3. The compound of claim 1, whereinthe compound is:

or corresponding carboxylic acid.
 4. The compound of claim 1, whereinthe compound is:

or corresponding carboxylic acid.
 5. The compound of claim 1, whereinthe compound is:

or corresponding carboxylic acid.
 6. The compound of claim 1, wherienthe compound is:

or corresponding carboxylic acid.
 7. The compound of claim 1, whereinthe compound is:

or corresponding carboxylic acid.
 8. The compound of claim 1, wherienthe compound is:

or corresponding carboxylic acid.
 9. The compound of claim 1, whereinthe compound is:

or corresponding carboxylic acid.
 10. The compound of claim 1, whereinthe compound is:

or corresponding carboxylic acid.
 11. The compound of claim 1, whereinthe compound is:

or corresponding carboxylic acid.
 12. The compound of claim 1, wherienthe compound is:

or corresponding carboxylic acid.
 13. The compound of claim 1, whereinthe compound is

or corresponding carboxylic acid.
 14. The compound of claim 1, whereinthe compound is

or corresponding carboxylic acid.
 15. The compound of claim 1, whereinthe compound is

or agriculturally acceptable derivative thereof.
 16. A herbicidalcomposition comprising an herbicidally effective amount of a compoundaccording to claim 1, in a mixture with an agriculturally acceptableadjuvant or carrier.
 17. A method of controlling undesirable vegetationwhich comprises applying an herbicidally effective amount of a compoundaccording to claim 1 where preemergence or postemergence control ofundesirable vegetation is desired.